Electrical microglial cell activation

ABSTRACT

A method is provided that includes positioning electrodes in or in contact with the head of a subject identified as in need of enhanced microglial cell activation. Control circuitry is activated to drive the electrodes to apply an electrical current to the brain of the subject, and to configure the electrical current to enhance microglial cell activation for taking up a substance from brain parenchyma. Other embodiments are also described.

CROSS-REFERENCE TO RELATED APPLICATIONS

The present application claims the benefit of U.S. ProvisionalApplication 62/444,939, filed Jan. 11, 2017, which is assigned to theassignee of the present application and is incorporated herein byreference.

FIELD OF THE APPLICATION

The present invention relates generally to treatment and prevention ofAlzheimer's disease and/or cerebral amyloid angiopathy (CAA), andspecifically to electrical techniques for treating, preventing, orslowing the progression of Alzheimer's disease and/or CAA.

BACKGROUND OF THE APPLICATION

Alzheimer's disease is a chronic neurodegenerative disease that causesdementia. Accumulation of substances such as amyloid beta and/or tauprotein in the brain is widely believed to contribute to the developmentof Alzheimer's disease.

US Patent Application Publication 2014/0324128 to Gross, which isassigned to the assignee of the present application and is incorporatedherein by reference, describes apparatus for driving fluid between firstand second anatomical sites of a subject. The apparatus comprises (1) afirst electrode, configured to be coupled to the first anatomical siteof the subject; (2) a second electrode, configured to be coupled to thesecond anatomical site of the subject; and (3) a control unit,configured to (i) detect a pressure difference between the first andsecond anatomical sites, and (ii) in response to the detected pressuredifference, drive fluid between the first and second anatomical sites byapplying a treatment voltage between the first and second electrodes.Other embodiments are also described.

SUMMARY OF THE APPLICATION

Some embodiments of the present invention provide techniques fortreating Alzheimer's disease and/or cerebral amyloid angiopathy (CAA).In some applications of the present invention, electrodes are positionedin or in contact with a head of a subject identified as in need ofenhanced microglial cell activation. Control circuitry is activated todrive the electrodes to apply an electrical current to a brain of thesubject, and to configure the electrical current to enhance microglialcell activation. This enhanced microglial cell activation generallycauses the microglia to increase uptake of amyloid beta from brainparenchymal, thereby treating, preventing, and/or slowing theprogression of Alzheimer's disease and/or CAA.

There is therefore provided, in accordance with an application of thepresent invention, a method including:

-   -   positioning electrodes in or in contact with the head of a        subject identified as in need of enhanced microglial cell        activation; and    -   activating control circuitry to drive the electrodes to apply an        electrical current to the brain of the subject, and to configure        the electrical current to enhance microglial cell activation for        taking up a substance from brain parenchyma.

For some applications, the substance is amyloid beta, and activating thecontrol circuitry includes activating the control circuitry to configurethe electrical current to enhance the microglial cell activation fortaking up the amyloid beta from the brain parenchyma.

For some applications, positioning the electrodes includes positioningthe electrodes in or in contact with the head of a subject identified asat risk of or suffering from Alzheimer's disease.

For some applications, positioning the electrodes includes positioningthe electrodes in or in contact with the head of a subject identified asat risk of or suffering from cerebral amyloid angiopathy (CAA).

For some applications, positioning the electrodes includes implanting atleast one of the electrodes intracranially. For some applications,implanting the at least one of the electrodes intracranially includesimplanting the at least one of the electrodes in brain parenchyma. Forsome applications:

-   -   the at least one of the electrodes is a parenchymal electrode,        and    -   positioning the electrodes further includes implanting at least        one cerebrospinal fluid (CSF) electrode of the electrodes in a        CSF-filled space of the brain, the CSF-filled space selected        from the group consisting of: a ventricular system and a        subarachnoid space, and    -   activating the control circuitry includes activating control        circuitry to drive the parenchymal and the CSF electrodes to        apply the electrical current to enhance the microglial cell        activation.

For some applications, implanting the at least one of the electrodesincludes implanting the at least one of the electrodes in electricalcontact with brain parenchyma. For some applications:

-   -   the at least one of the electrodes is a parenchymal electrode,        and    -   positioning the electrodes further includes implanting at least        one cerebrospinal fluid (CSF) electrode of the electrodes in a        CSF-filled space of the brain, the CSF-filled space selected        from the group consisting of: a ventricular system and a        subarachnoid space, and    -   activating the control circuitry includes activating control        circuitry to drive the parenchymal and the CSF electrodes to        apply the electrical current to enhance the microglial cell        activation.

For some applications, implanting at least one of the electrodesintracranially includes implanting the at least one of the electrodes ina CSF-filled space of the brain, the CSF-filled space selected from thegroup consisting of: a ventricular system and a subarachnoid space.

For some applications, positioning the electrodes includes positioningat least one of the electrodes outside and in electrical contact with askull of the head. For some applications, implanting the at least one ofthe electrodes includes implanting the at least one of the electrodesunder skin of the head. For some applications, positioning the at leastone of the electrodes outside and in electrical contact with a skull ofthe head includes:

-   -   positioning one or more midplane treatment electrodes over a        superior sagittal sinus, outside and in electrical contact with        the skull; and    -   positioning one or more lateral treatment electrodes between 1        and 12 cm of a sagittal midplane of the skull.        For some applications, activating the control circuitry includes        activating the control circuitry to configure the electrical        current to enhance the microglial cell activation and to        electroosmotically drive fluid from a subarachnoid space to the        superior sagittal sinus, by applying one or more treatment        currents between (a) one or more of the one or more midplane        treatment electrodes and (b) one or more of the one or more        lateral treatment electrodes.

For some applications, positioning the electrodes includes positioningat least one of the electrodes on an external surface of skin of thehead.

For some applications, activating the control circuitry includesactivating the control circuitry to configure the electrical current tohave a frequency of between 10 and 90 Hz.

For some applications, activating the control circuitry includesactivating the control circuitry to apply the electrical current inpulses having an average pulse duration of between 0.1 ms and 10 ms.

For some applications, activating the control circuitry includesactivating the control circuitry to apply the electrical current inpulses with a duty cycle of between 1% and 50%.

For some applications, activating the control circuitry includesactivating the control circuitry to apply the electrical current with anaverage amplitude of between 0.1 and 5 mA.

For some applications, activating the control circuitry includesactivating the control circuitry to apply the electrical current with anaverage voltage that results in between 0.1 and 5 mA current.

For some applications, activating the control circuitry includesactivating the control circuitry to configure the electrical current toenhance the microglial cell activation and to enhance clearance of thesubstance from brain parenchyma to outside the brain parenchyma. Forsome applications, activating the control circuitry to configure theelectrical current to enhance the clearance of the substance from thebrain parenchyma to outside the brain parenchyma includes activating thecontrol circuitry to configure the electrical current to clear thesubstance from the brain parenchyma to a CSF-filled space of the brainselected from the group consisting of: a ventricular system and asubarachnoid space.

For some applications, activating the control circuitry to configure theelectrical current to enhance the clearance of the substance from thebrain parenchyma to outside the brain parenchyma includes activating thecontrol circuitry to configure the electrical current to clear thesubstance by driving fluid from the CSF-filled space of the brain to asuperior sagittal sinus of the brain.

For some applications, the substance is amyloid beta, and activating thecontrol circuitry includes activating the control circuitry to configurethe electrical current to enhance the clearance of the amyloid beta fromthe brain parenchyma to outside the brain parenchyma.

For some applications, activating the control circuitry includes:

-   -   activating the control circuitry to configure the electrical        current to enhance the microglial cell activation with a first        duty cycle during a treatment period having a duration of at        least one hour, and    -   activating the control circuitry to configure the electrical        current to enhance the clearance of the substance from the brain        parenchyma to outside the brain parenchyma with a second duty        cycle during the treatment period,    -   the second duty cycle is greater than the first duty cycle.

For some applications, activating the control circuitry includes:

-   -   activating the control circuitry to configure the electrical        current to enhance the microglial cell activation intermittently        during the treatment period, and    -   activating the control circuitry to configure the electrical        current to enhance the clearance of the substance from the brain        parenchyma to outside the brain parenchyma generally        continuously during the treatment period.

For some applications, activating the control circuitry to configure theelectrical current to enhance the microglial cell activation includesactivating the control circuitry to configure the electrical current toenhance the microglial cell activation during activation periodsalternating with rest periods, the rest periods have an average durationgreater than one hour. For some applications, the activation periodshave an average duration of less than one hour.

For some applications:

-   -   activating the control circuitry to configure the electrical        current to enhance the microglial cell activation includes        activating the control circuitry to configure the electrical        current as alternating current, and    -   activating the control circuitry to configure the electrical        current to enhance clearance of the substance from the brain        parenchyma to outside the brain parenchyma includes activating        the control circuitry to configure the electrical current as        direct current.

For some applications:

-   -   activating the control circuitry to configure the electrical        current to enhance the microglial cell activation includes        activating the control circuitry to configure the electrical        current as direct current, and    -   activating the control circuitry to configure the electrical        current to enhance clearance of the substance from the brain        parenchyma to outside the brain parenchyma includes activating        the control circuitry to configure the electrical current as        direct current.

For some applications, activating the control circuitry includesactivating the control circuitry to:

-   -   drive the electrodes to apply the electrical current during at        least a first treatment period and a second treatment period,        and    -   provide a rest period between the first and the second treatment        periods, the rest period having a duration of at least 12 hours,        such as at least 30 hours, at least 48 hours, or at least 72        hours.

There is further provided, in accordance with an application of thepresent invention, apparatus including:

-   -   electrodes, which are configured to be positioned in or in        contact with the head of a subject identified as in need of        enhanced microglial cell activation; and    -   control circuitry, which is configured to drive the electrodes        to apply an electrical current to the brain of the subject, and        to configure the electrical current to enhance microglial cell        activation for taking up a substance from brain parenchyma.

The control circuitry may be configured and/or activated to implementany of the features of the methods described above.

The methods and apparatus described above may be implemented incombination with any of the following inventive concepts 1-116, mutatismutandis:

There is further provided, in accordance with an inventive concept 1 ofthe present invention, apparatus comprising:

-   -   a parenchymal electrode, configured to be implanted in brain        parenchyma of a subject identified as at risk of or suffering        from a disease;    -   a cerebrospinal fluid (CSF) electrode, configured to be        implanted in a CSF-filled space of a brain of the subject, the        CSF-filled space selected from the group consisting of: a        ventricular system and a subarachnoid space; and    -   control circuitry, configured to drive the parenchymal and the        CSF electrodes to clear a substance from the brain parenchyma        into the CSF-filled space of the brain.

There is further provided, in accordance with an inventive concept 2 ofthe present invention, apparatus comprising:

-   -   a parenchymal electrode, configured to be implanted in        electrical contact with brain parenchyma of a subject identified        as at risk of or suffering from a disease;    -   a cerebrospinal fluid (CSF) electrode, configured to be        implanted in a CSF-filled space of a brain of the subject, the        CSF-filled space selected from the group consisting of: a        ventricular system and a subarachnoid space; and    -   control circuitry, configured to drive the parenchymal and the        CSF electrodes to clear a substance from the brain parenchyma        into the CSF-filled space of the brain.        Inventive concept 3. The apparatus according to any one of        inventive concepts 1-2, wherein the disease is Alzheimer's        disease, and wherein the parenchymal electrode is configured to        be implanted in the subject identified as at risk of or        suffering from Alzheimer's disease.        Inventive concept 4. The apparatus according to any one of        inventive concepts 1-2, wherein the disease is cerebral amyloid        angiopathy (CAA), and wherein the parenchymal electrode is        configured to be implanted in the subject identified as at risk        of or suffering from CAA.        Inventive concept 5. The apparatus according to any one of        inventive concepts 1-2, wherein the CSF-filled space of the        brain is the ventricular system, and wherein the CSF electrode        is a ventricular electrode, configured to be implanted in the        ventricular system.        Inventive concept 6. The apparatus according to any one of        inventive concepts 1-2, wherein the CSF-filled space of the        brain is the subarachnoid space, and wherein the CSF electrode        is a subarachnoid electrode, configured to be implanted in the        subarachnoid space.        Inventive concept 7. The apparatus according to any one of        inventive concepts 1-2, wherein the substance includes amyloid        beta, and wherein the control circuitry is configured to drive        the parenchymal and the CSF electrodes to clear the amyloid beta        from the brain parenchyma into the CSF-filled space of the        brain.        Inventive concept 8. The apparatus according to any one of        inventive concepts 1-2, wherein the substance includes metal        ions, and wherein the control circuitry is configured to drive        the parenchymal and the CSF electrodes to clear the metal ions        from the brain parenchyma into the CSF-filled space of the        brain.        Inventive concept 9. The apparatus according to any one of        inventive concepts 1-2, wherein the substance includes tau        protein, and wherein the control circuitry is configured to        drive the parenchymal and the CSF electrodes to clear the tau        protein from the brain parenchyma into the CSF-filled space of        the brain.        Inventive concept 10. The apparatus according to any one of        inventive concepts 1-2, wherein the parenchymal electrode is        configured to be implanted in white matter of the brain.        Inventive concept 11. The apparatus according to any one of        inventive concepts 1-2, wherein the control circuitry is        configured to configure the parenchymal electrode to be an        anode, and the CSF electrode to be a cathode.        Inventive concept 12. The apparatus according to any one of        inventive concepts 1-2, wherein the control circuitry is        configured to configure the parenchymal electrode to be a        cathode, and the CSF electrode to be an anode.        Inventive concept 13. The apparatus according to any one of        inventive concepts 1-2, wherein the control circuitry is        configured to additionally apply deep brain stimulation using        the parenchymal electrode.        Inventive concept 14. The apparatus according to any one of        inventive concepts 1-2, wherein the control circuitry is        configured to be implanted under skin of the subject.        Inventive concept 15. The apparatus according to any one of        inventive concepts 1-2, wherein the control circuitry is        configured to drive the parenchymal and the CSF electrodes to        clear the substance by applying a non-excitatory current between        the parenchymal and the CSF electrodes.        Inventive concept 16. The apparatus according to any one of        inventive concepts 1-2, wherein the control circuitry is        configured to drive the parenchymal and the CSF electrodes to        clear the substance by applying direct current between the        parenchymal and the CSF electrodes.        Inventive concept 17. The apparatus according to inventive        concept 16, wherein the control circuitry is configured to apply        the direct current with an average amplitude of between 1 and 5        mA.        Inventive concept 18. The apparatus according to inventive        concept 16, wherein the control circuitry is configured to apply        the direct current with an average amplitude of less than 1.2 V.        Inventive concept 19. The apparatus according to inventive        concept 16, wherein the control circuitry is configured to apply        the direct current as a series of pulses.        Inventive concept 20. The apparatus according to inventive        concept 19, wherein the control circuitry is configured to apply        the direct current as the series of pulses having an average        pulse duration of between 100 milliseconds and 300 seconds.        Inventive concept 21. The apparatus according to inventive        concept 19, wherein the control circuitry is configured to apply        the direct current as the series of pulses with a duty cycle of        between 1% and 50%.        Inventive concept 22. The apparatus according to inventive        concept 19, wherein the control unit is configured to:    -   drive the parenchymal and the CSF electrodes to clear the        substance by applying a voltage between the parenchymal and the        CSF electrodes during each of the pulses,    -   while applying the voltage, measure a current resulting from        application of the voltage during the pulse, and    -   terminate the pulse upon the measured current falling below a        threshold value.        Inventive concept 23. The apparatus according to inventive        concept 22, wherein the threshold value is based on an initial        current magnitude measured upon commencement of the pulse.        Inventive concept 24. The apparatus according to any one of        inventive concepts 1-2, further comprising a midplane treatment        electrode, adapted to be disposed in or over a superior sagittal        sinus, wherein the control circuitry is configured to clear the        substance from the CSF-filled space of the brain to the superior        sagittal sinus, by applying a treatment current between the        midplane treatment electrode and the CSF electrode.        Inventive concept 25. The apparatus according to inventive        concept 24, wherein the midplane treatment electrode is adapted        to be disposed over the superior sagittal sinus.        Inventive concept 26. The apparatus according to inventive        concept 25, wherein the midplane treatment electrode is adapted        to be disposed over the superior sagittal sinus, outside and in        electrical contact with a skull of a head of the subject.        Inventive concept 27. The apparatus according to inventive        concept 25, wherein the midplane treatment electrode is adapted        to be disposed over the superior sagittal sinus, under a skull        of a head of the subject.        Inventive concept 28. The apparatus according to inventive        concept 24, wherein the midplane treatment electrode is adapted        to be implanted in the superior sagittal sinus.        Inventive concept 29. The apparatus according to inventive        concept 24, wherein the CSF electrode is adapted to be disposed        between 1 and 12 cm of a sagittal midplane of a skull of the        subject.        Inventive concept 30. The apparatus according to inventive        concept 24,    -   wherein the CSF-filled space of the brain is the subarachnoid        space,    -   wherein the CSF electrode is a subarachnoid electrode,        configured to be implanted in the subarachnoid space, and    -   wherein the control circuitry is configured to clear the        substance from the subarachnoid space to the superior sagittal        sinus.        Inventive concept 31. The apparatus according to inventive        concept 24, wherein the control circuitry is configured to clear        the substance by electroosmotically driving fluid from the        CSF-filled space of the brain to the superior sagittal sinus.        Inventive concept 32. The apparatus according to inventive        concept 31, wherein the control circuitry is configured to drive        the fluid from the CSF-filled space of the brain to the superior        sagittal sinus by configuring the midplane treatment electrode        as a cathode, and the CSF electrode as an anode.        Inventive concept 33. The apparatus according to inventive        concept 24, wherein the control circuitry is configured to clear        the substance by electrophoretically driving the substance from        the CSF-filled space of the brain to the superior sagittal        sinus.        Inventive concept 34. The apparatus according to inventive        concept 24, wherein the control circuitry is configured to apply        the treatment current as direct current.        Inventive concept 35. The apparatus according to inventive        concept 24, wherein the control circuitry is configured to        simultaneously drive (a) the parenchymal and the CSF electrodes        to clear the substance from the brain parenchyma into the        CSF-filled space of the brain, and (b) apply the treatment        current between the midplane treatment electrode and the CSF        electrode to clear the substance from the CSF-filled space to        the superior sagittal sinus.        Inventive concept 36. The apparatus according to inventive        concept 35, wherein the control circuitry is configured to apply        first, second, and third voltages to the parenchymal electrode,        the CSF electrode, and the midplane treatment electrode,        respectively, the third voltage more positive than the second        voltage, which is in turn more positive than first voltage.        Inventive concept 37. The apparatus according to inventive        concept 24, wherein the control circuitry is configured to        alternatingly (a) drive the parenchymal and the CSF electrodes        to clear the substance from the brain parenchyma into the        CSF-filled space of the brain, and (b) apply the treatment        current between the midplane treatment electrode and the CSF        electrode to clear the substance from the CSF-filled space to        the superior sagittal sinus.        Inventive concept 38. The apparatus according to any one of        inventive concepts 1-2,    -   wherein the cerebrospinal fluid (CSF) electrode is a first a        cerebrospinal fluid (CSF) electrode,    -   wherein the apparatus further comprises:        -   a midplane treatment electrode, adapted to be disposed in or            over a superior sagittal sinus; and        -   a second cerebrospinal fluid (CSF) electrode, configured to            be implanted in a CSF-filled space of a brain of the            subject, the CSF-filled space selected from the group            consisting of: a ventricular system and a subarachnoid            space, and    -   wherein the control circuitry is configured to clear the        substance from the CSF-filled space of the brain to the superior        sagittal sinus, by applying a treatment current between (a) the        midplane treatment electrode and (b) the second CSF electrode.        Inventive concept 39. The apparatus according to inventive        concept 38, wherein the midplane treatment electrode is adapted        to be disposed over the superior sagittal sinus.        Inventive concept 40. The apparatus according to inventive        concept 39, wherein the midplane treatment electrode is adapted        to be disposed over the superior sagittal sinus, outside and in        electrical contact with a skull of a head of the subject.        Inventive concept 41. The apparatus according to inventive        concept 39, wherein the midplane treatment electrode is adapted        to be disposed over the superior sagittal sinus, under a skull        of a head of the subject.        Inventive concept 42. The apparatus according to inventive        concept 38, wherein the midplane treatment electrode is adapted        to be implanted in the superior sagittal sinus.        Inventive concept 43. The apparatus according to any one of        inventive concepts 1-2, further comprising:    -   midplane treatment electrodes, adapted to be disposed over a        superior sagittal sinus; and    -   lateral treatment electrodes, adapted to be disposed between 1        and 12 cm of a sagittal midplane of a skull of a head of the        subject,    -   wherein the control circuitry is configured to clear the        substance from the subarachnoid space to the superior sagittal        sinus, by applying one or more treatment currents between (a)        one or more of the midplane treatment electrodes and (b) one or        more of the lateral treatment electrodes.        Inventive concept 44. The apparatus according to inventive        concept 43, wherein the midplane treatment electrodes are        adapted to be disposed over the superior sagittal sinus, outside        and in electrical contact with a skull of a head of the subject.        Inventive concept 45. The apparatus according to inventive        concept 43, wherein the midplane treatment electrodes are        adapted to be disposed over the superior sagittal sinus, under a        skull of a head of the subject.        Inventive concept 46. The apparatus according to inventive        concept 43, wherein the control circuitry is configured to clear        the substance by electroosmotically driving fluid from the        subarachnoid space to the superior sagittal sinus.        Inventive concept 47. The apparatus according to inventive        concept 46, wherein the control circuitry is configured to        configure the midplane treatment electrodes as cathodes, and the        lateral treatment electrodes as anodes.        Inventive concept 48. The apparatus according to inventive        concept 46,    -   wherein the lateral treatment electrodes comprise (a) left        lateral treatment electrodes, which are adapted to be disposed        left of the sagittal midplane of the skull, and (b) right        lateral treatment electrodes, which are adapted to be disposed        right of the sagittal midplane of the skull, and    -   wherein the control circuitry is configured to configure the        midplane treatment electrodes as cathodes, and the left and the        right lateral treatment electrodes as left and right anodes,        respectively.        Inventive concept 49. The apparatus according to inventive        concept 43, wherein the control circuitry is configured to clear        the substance by electrophoretically driving the substance from        the subarachnoid space to the superior sagittal sinus.        Inventive concept 50. The apparatus according to inventive        concept 49,    -   wherein the lateral treatment electrodes comprise (a) left        lateral treatment electrodes, which are adapted to be disposed        left of the sagittal midplane of the skull, and (b) right        lateral treatment electrodes, which are adapted to be disposed        right of the sagittal midplane of the skull, and    -   wherein the control circuitry is configured to configure the        midplane treatment electrodes as anodes, and the left and the        right lateral treatment electrodes as left and right cathodes,        respectively.        Inventive concept 51. The apparatus according to inventive        concept 43, wherein the lateral treatment electrodes are adapted        to be implanted under an arachnoid mater of the subject.        Inventive concept 52. The apparatus according to inventive        concept 51, wherein the lateral treatment electrodes are adapted        to be disposed in the subarachnoid space.        Inventive concept 53. The apparatus according to inventive        concept 51, wherein the lateral treatment electrodes are adapted        to be disposed in gray or white matter of a brain of the        subject.        Inventive concept 54. The apparatus according to inventive        concept 43, wherein the control circuitry is configured to apply        the one or more treatment currents as direct currents.

There is still further provided, in accordance with an inventive concept55 of the present invention, a method comprising:

-   -   implanting a parenchymal electrode in electrical contact with        brain parenchyma of a subject identified as at risk of or        suffering from a disease;    -   implanting a cerebrospinal fluid (CSF) electrode in a CSF-filled        space of a brain of the subject, the CSF-filled space selected        from the group consisting of: a ventricular system and a        subarachnoid space; and    -   activating control circuitry to drive the parenchymal and the        CSF electrodes to clear a substance from the brain parenchyma        into the CSF-filled space of the brain.        Inventive concept 56. The method according to inventive concept        55, wherein the disease is Alzheimer's disease, and wherein        implanting the parenchymal electrode comprises implanting the        parenchymal electrode in the subject identified as at risk of or        suffering from Alzheimer's disease.        Inventive concept 57. The method according to inventive concept        55, wherein the disease is cerebral amyloid angiopathy (CAA),        and wherein implanting the parenchymal electrode comprises        implanting the parenchymal electrode in the subject identified        as at risk of or suffering from CAA.        Inventive concept 58. The method according to inventive concept        55, wherein the CSF-filled space of the brain is the ventricular        system, wherein the CSF electrode is a ventricular electrode,        and wherein activating the control circuitry comprises        activating the control circuitry to drive the parenchymal and        the ventricular electrodes to clear the substance from the brain        parenchyma into the ventricular system.        Inventive concept 59. The method according to inventive concept        55, wherein the CSF-filled space of the brain is the        subarachnoid space, wherein the CSF electrode is a subarachnoid        electrode, and wherein activating the control circuitry        comprises activating the control circuitry to drive the        parenchymal and the subarachnoid electrodes to clear the        substance from the brain parenchyma into the subarachnoid space.        Inventive concept 60. The method according to inventive concept        55, wherein the substance includes amyloid beta, and wherein        activating the control circuitry comprises activating the        control circuitry to drive the parenchymal and the CSF        electrodes to clear the amyloid beta from the brain parenchyma        into the CSF-filled space of the brain.        Inventive concept 61. The method according to inventive concept        55, wherein the substance includes metal ions, and wherein        activating the control circuitry comprises activating the        control circuitry to drive the parenchymal and the CSF        electrodes to clear the metal ions from the brain parenchyma        into the CSF-filled space of the brain.        Inventive concept 62. The method according to inventive concept        55, wherein the substance includes tau protein, and wherein        activating the control circuitry comprises activating the        control circuitry to drive the parenchymal and the CSF        electrodes to clear the tau protein from the brain parenchyma        into the CSF-filled space of the brain.        Inventive concept 63. The method according to inventive concept        55, wherein implanting the parenchymal electrode in electrical        contact with the brain parenchyma comprises implanting the        parenchymal electrode in the brain parenchyma.        Inventive concept 64. The method according to inventive concept        63, wherein implanting the parenchymal electrode in the brain        parenchyma comprises implanting the parenchymal electrode in        white matter of the brain.        Inventive concept 65. The method according to inventive concept        63, wherein implanting the parenchymal and the CSF electrodes        comprises implanting the parenchymal and the CSF electrodes such        that an area of build-up of the substance is between the        parenchymal and the CSF electrodes.        Inventive concept 66. The method according to inventive concept        65, wherein implanting the parenchymal and the CSF electrodes        comprises identifying the area of build-up of the substance in        the brain parenchyma before implanting the parenchymal and the        CSF electrodes.        Inventive concept 67. The method according to inventive concept        66, wherein identifying the area of build-up comprises        performing imaging of the brain.        Inventive concept 68. The method according to inventive concept        67, wherein performing the imaging comprises performing        functional MRI (fMRI) imaging of the brain.        Inventive concept 69. The method according to inventive concept        63, wherein implanting the parenchymal electrode comprises        implanting the parenchymal electrode such that an area of        build-up of the substance is between the parenchymal electrode        and an area of the CSF-filled space of the brain nearest the        area of build-up.        Inventive concept 70. The method according to inventive concept        69, wherein implanting the parenchymal electrode comprises        identifying the area of build-up of the substance in the brain        parenchyma before implanting the parenchymal electrode.        Inventive concept 71. The method according to inventive concept        70, wherein identifying the area of build-up comprises        performing imaging of the brain.        Inventive concept 72. The method according to inventive concept        71, wherein performing the imaging comprises performing        functional MRI (fMRI) imaging of the brain.        Inventive concept 73. The method according to inventive concept        55, wherein activating the control circuitry comprises        activating the control circuitry to configure the parenchymal        electrode to be an anode, and the CSF electrode to be a cathode.        Inventive concept 74. The method according to inventive concept        55, wherein activating the control circuitry comprises        activating the control circuitry to configure the parenchymal        electrode to be a cathode, and the CSF electrode to be an anode.        Inventive concept 75. The method according to inventive concept        55, further comprising applying deep brain stimulation using the        parenchymal electrode.        Inventive concept 76. The method according to inventive concept        55, further comprising implanting the control circuitry under        skin of the subject.        Inventive concept 77. The method according to inventive concept        55, wherein activating the control circuitry to drive the        parenchymal and the CSF electrodes comprises activating the        control circuitry to drive the parenchymal and the CSF        electrodes to clear the substance by applying a non-excitatory        current between the parenchymal and the CSF electrodes.        Inventive concept 78. The method according to inventive concept        55, wherein activating the control circuitry to drive the        parenchymal and the CSF electrodes comprises activating the        control circuitry to drive the parenchymal and the CSF        electrodes to clear the substance by applying direct current        between the parenchymal and the CSF electrodes.        Inventive concept 79. The method according to inventive concept        78, wherein activating the control circuitry to apply the direct        current comprises activating the control circuitry to apply the        direct current with an average amplitude of between 1 and 5 mA.        Inventive concept 80. The method according to inventive concept        78, wherein activating the control circuitry to apply the direct        current comprises activating the control circuitry to apply the        direct current with an average amplitude of less than 1.2 V.        Inventive concept 81. The method according to inventive concept        78, wherein activating the control circuitry to apply the direct        current comprises activating the control circuitry to apply the        direct current as a series of pulses.        Inventive concept 82. The method according to inventive concept        81, wherein activating the control circuitry to apply the direct        current as the series of pulses comprises activating the control        circuitry to apply the direct current as the series of pulses        having an average pulse duration of between 100 milliseconds and        300 seconds.        Inventive concept 83. The method according to inventive concept        81, wherein activating the control circuitry to apply the direct        current as the series of pulses comprises activating the control        circuitry to apply the direct current as the series of pulses        with a duty cycle of between 1% and 50%.        Inventive concept 84. The method according to inventive concept        81, wherein activating the control circuitry to drive the        parenchymal and the CSF electrodes comprises activating the        control unit to:    -   drive the parenchymal and the CSF electrodes to clear the        substance by applying a voltage between the parenchymal and the        CSF electrodes during each of the pulses,    -   while applying the voltage, measure a current resulting from        application of the voltage during the pulse, and    -   terminate the pulse upon the measured current falling below a        threshold value.        Inventive concept 85. The method according to inventive concept        84, wherein the threshold value is based on an initial current        magnitude measured upon commencement of the pulse.        Inventive concept 86. The method according to inventive concept        55,    -   further comprising disposing a midplane treatment electrode in        or over a superior sagittal sinus,    -   wherein activating the control circuitry comprises activating        the control circuitry to clear the substance from the CSF-filled        space of the brain to the superior sagittal sinus, by applying a        treatment current between the midplane treatment electrode and        the CSF electrode.        Inventive concept 87. The method according to inventive concept        86, wherein disposing the midplane treatment electrode comprises        disposing the midplane treatment electrode over the superior        sagittal sinus.        Inventive concept 88. The method according to inventive concept        87, wherein disposing the midplane treatment electrode comprises        disposing the midplane treatment electrode over the superior        sagittal sinus, outside and in electrical contact with a skull        of a head of the subject.        Inventive concept 89. The method according to inventive concept        87, wherein disposing the midplane treatment electrode comprises        disposing the midplane treatment electrode over the superior        sagittal sinus, under a skull of a head of the subject.        Inventive concept 90. The method according to inventive concept        86, wherein disposing the midplane treatment electrode comprises        implanting the midplane treatment electrode in the superior        sagittal sinus.        Inventive concept 91. The method according to inventive concept        86, wherein implanting the CSF electrode comprises implanting        the CSF electrode between 1 and 12 cm of a sagittal midplane of        a skull of the subject.        Inventive concept 92. The method according to inventive concept        86,    -   wherein the CSF-filled space of the brain is the subarachnoid        space,    -   wherein the CSF electrode is a subarachnoid electrode, and    -   wherein activating the control circuitry comprises activating        the control circuitry to clear the substance from the        subarachnoid space to the superior sagittal sinus.        Inventive concept 93. The method according to inventive concept        86, wherein activating the control circuitry comprises        activating the control circuitry to clear the substance by        electroosmotically driving fluid from the CSF-filled space of        the brain to the superior sagittal sinus.        Inventive concept 94. The method according to inventive concept        93, wherein activating the control circuitry comprises        activating the control circuitry to drive the fluid from the        CSF-filled space of the brain to the superior sagittal sinus by        configuring the midplane treatment electrode as a cathode, and        the CSF electrode as an anode.        Inventive concept 95. The method according to inventive concept        86, wherein activating the control circuitry comprises        activating the control circuitry to clear the substance by        electrophoretically driving the substance from the CSF-filled        space of the brain to the superior sagittal sinus.        Inventive concept 96. The method according to inventive concept        86, wherein activating the control circuitry comprises        activating the control circuitry to apply the treatment current        as direct current.        Inventive concept 97. The method according to inventive concept        86, wherein activating the control circuitry comprises        activating the control circuitry to simultaneously drive (a) the        parenchymal and the CSF electrodes to clear the substance from        the brain parenchyma into the CSF-filled space of the brain,        and (b) apply the treatment current between the midplane        treatment electrode and the CSF electrode to clear the substance        from the CSF-filled space to the superior sagittal sinus.        Inventive concept 98. The method according to inventive concept        97, wherein activating the control circuitry comprises        activating the control circuitry to apply first, second, and        third voltages to the parenchymal electrode, the CSF electrode,        and the midplane treatment electrode, respectively, the third        voltage more positive than the second voltage, which is in turn        more positive than first voltage.        Inventive concept 99. The method according to inventive concept        86, wherein activating the control circuitry comprises        activating the control circuitry to alternatingly (a) drive the        parenchymal and the CSF electrodes to clear the substance from        the brain parenchyma into the CSF-filled space of the brain,        and (b) apply the treatment current between the midplane        treatment electrode and the CSF electrode to clear the substance        from the CSF-filled space to the superior sagittal sinus.        Inventive concept 100. The method according to inventive concept        55,    -   wherein the cerebrospinal fluid (CSF) electrode is a first a        cerebrospinal fluid (CSF) electrode,    -   wherein the method further comprises:        -   disposing a midplane treatment electrode in or over a            superior sagittal sinus; and        -   implanting a second cerebrospinal fluid (CSF) electrode in a            CSF-filled space of a brain of the subject, the CSF-filled            space selected from the group consisting of: a ventricular            system and a subarachnoid space, and    -   wherein activating the control circuitry comprises activating        the control circuitry to clear the substance from the CSF-filled        space of the brain to the superior sagittal sinus, by applying a        treatment current between (a) the midplane treatment electrode        and (b) the second CSF electrode.        Inventive concept 101. The method according to inventive concept        100, wherein disposing the midplane treatment electrode        comprises disposing the midplane treatment electrode over the        superior sagittal sinus.        Inventive concept 102. The method according to inventive concept        101, wherein disposing the midplane treatment electrode        comprises disposing the midplane treatment electrode over the        superior sagittal sinus, outside and in electrical contact with        a skull of a head of the subject.        Inventive concept 103. The method according to inventive concept        101, wherein disposing the midplane treatment electrode        comprises disposing the midplane treatment electrode over the        superior sagittal sinus, under a skull of a head of the subject.        Inventive concept 104. The method according to inventive concept        100, wherein disposing the midplane treatment electrode        comprises implanting the midplane treatment electrode in the        superior sagittal sinus.        Inventive concept 105. The method according to inventive concept        55, further comprising:    -   disposing midplane treatment electrodes over a superior sagittal        sinus; and    -   disposing lateral treatment electrodes between 1 and 12 cm of a        sagittal midplane of a skull of a head of the subject,    -   wherein activating the control circuitry comprises activating        the control circuitry to clear the substance from the        subarachnoid space to the superior sagittal sinus, by applying        one or more treatment currents between (a) one or more of the        midplane treatment electrodes and (b) one or more of the lateral        treatment electrodes.        Inventive concept 106. The method according to inventive concept        105, wherein disposing the midplane treatment electrodes        comprises disposing the midplane treatment electrodes over the        superior sagittal sinus, outside and in electrical contact with        a skull of a head of the subject.        Inventive concept 107. The method according to inventive concept        105, wherein disposing the midplane treatment electrodes        comprises disposing the midplane treatment electrodes over the        superior sagittal sinus, under a skull of a head of the subject.        Inventive concept 108. The method according to inventive concept        105, wherein activating the control circuitry comprises        activating the control circuitry to clear the substance by        electroosmotically driving fluid from the subarachnoid space to        the superior sagittal sinus.        Inventive concept 109. The method according to inventive concept        108, wherein activating the control circuitry comprises        activating the control circuitry to configure the midplane        treatment electrodes as cathodes, and the lateral treatment        electrodes as anodes.        Inventive concept 110. The method according to inventive concept        108,    -   wherein the lateral treatment electrodes include left lateral        treatment electrodes and right lateral treatment electrodes,    -   wherein disposing the lateral treatment electrodes includes        disposing the left lateral treatment electrodes left of the        sagittal midplane of the skull, and disposing the right lateral        treatment electrodes right of the sagittal midplane of the        skull, and    -   wherein activating the control circuitry includes activating the        control circuitry to configure the midplane treatment electrodes        as cathodes, and the left and the right lateral treatment        electrodes as left and right anodes, respectively        Inventive concept 111. The method according to inventive concept        105, wherein activating the control circuitry comprises        activating the control circuitry to clear the substance by        electrophoretically driving the substance from the subarachnoid        space to the superior sagittal sinus.        Inventive concept 112. The method according to inventive concept        111,    -   wherein the lateral treatment electrodes include left lateral        treatment electrodes and right lateral treatment electrodes,    -   wherein disposing the lateral treatment electrodes includes        disposing the left lateral treatment electrodes left of the        sagittal midplane of the skull, and disposing the right lateral        treatment electrodes right of the sagittal midplane of the        skull, and    -   wherein activating the control circuitry includes activating the        control circuitry to configure the midplane treatment electrodes        as anodes, and the left and the right lateral treatment        electrodes as left and right cathodes, respectively.        Inventive concept 113. The method according to inventive concept        105, wherein disposing the lateral treatment electrodes        comprises implanting the lateral treatment electrodes under an        arachnoid mater of the subject.        Inventive concept 114. The method according to inventive concept        113, wherein disposing the lateral treatment electrodes        comprises disposing the lateral treatment electrodes in the        subarachnoid space.        Inventive concept 115. The method according to inventive concept        113, wherein disposing the lateral treatment electrodes        comprises disposing the lateral treatment electrodes in gray or        white matter of a brain of the subject.        Inventive concept 116. The method according to inventive concept        105, wherein activating the control circuitry comprises        activating the control circuitry to apply the one or more        treatment currents as direct currents.

The present invention will be more fully understood from the followingdetailed description of embodiments thereof, taken together with thedrawings, in which:

BRIEF DESCRIPTION OF THE DRAWINGS

FIGS. 1A-C are schematic illustrations of a system for treatingAlzheimer's disease, in accordance with respective applications of thepresent invention;

FIGS. 2A-B are schematic illustrations of cross-sections of a rat brainshowing results of an animal experiment performed in accordance with anapplication of the present invention;

FIG. 3 is a graph showing results of an in vitro experiment performed inaccordance with an application of the present invention; and

FIGS. 4A-G are schematic illustrations of alternative configurations ofthe system of FIGS. 1A-C, in accordance with respective applications ofthe present invention.

DETAILED DESCRIPTION OF APPLICATIONS

FIGS. 1A-C are schematic illustrations of a system 20 for treatingAlzheimer's disease and/or cerebral amyloid angiopathy (CAA), inaccordance with respective applications of the present invention. System20 comprises electrodes, which are configured to positioned in or incontact with a head 174 of a subject identified as in need of enhancedmicroglial cell activation, such as because the subject is identified asat risk of or suffering from Alzheimer's disease and/or CAA. For someapplications, the electrodes comprise one or more parenchymal electrodes30 and/or one or more cerebrospinal fluid (CSF) electrodes 32. System 20further comprises control circuitry 34, which is electrically coupled tothe electrodes. In configuration in which the electrodes compriseparenchymal and CSF electrodes 30 and 32, system 20 is typically coupledto the electrodes by parenchymal and CSF electrode leads 36 and 38,respectively. For some applications, at least one of the electrodes isattached to an external surface of a casing containing control circuitry34, or the casing includes a conductive external surface that serves asat least one of the electrodes; the casing may be implantable.

In some applications of the present invention, control circuitry 34 isactivated to drive the electrodes to apply an electrical current to abrain 52 of the subject, and to configure the electrical current toenhance microglial cell activation for taking up a substance, such asamyloid beta and/or tau protein, from brain parenchyma 50, so as toclear the substance from brain parenchyma 50. For some applications,control circuitry 34 is activated to configure the electrical current tosynchronize and/or enhance gamma oscillations in brain 52.

For some applications, control circuitry 34 is activated to (a) drivethe electrodes to apply the electrical current during at least a firsttreatment period and a second treatment period, and (b) provide a restperiod between the first and the second treatment periods, the restperiod having a duration of at least 12 hours, such as at least 24hours, at least 30 hours (i.e., greater than a length of a typicalcircadian cycle), at least 30 hours, at least 48 hours, at least 72hours, at least a week, or at least a month. The inventors hypothesizethat the induced microglia activation lasts for perhaps days, weeks, oreven a month after termination of the application of the electricalcurrent that caused the activation.

For some applications, control circuitry 34 is activated to configurethe electrical current to have a frequency of at least 10 Hz, no morethan 90 Hz, and/or between 10 and 90 Hz. For some applications, controlcircuitry 34 is activated to apply the direct current as a series ofpulses. For some applications, the series of pulses has an average pulseduration of at least 0.1 milliseconds, no more than 10 milliseconds,and/or between 0.1 and 10 milliseconds. For some applications, controlcircuitry 34 is activated to apply the electrical current with anaverage amplitude of at least 0.1 mA, no more than 5 mA, and/or between0.1 and 5 mA. For some applications, control circuitry 34 is activatedto apply the electrical current in pulses with a duty cycle of at least1%, no more than 50%, and/or between 1% and 50%. For some applications,control circuitry 34 is activated to apply the electrical current withan average voltage that results in at least 0.1 mA, no more than 5 mA,and/or between 0.1 and 5 mA current.

In some applications of the present invention, as shown for two ofparenchymal electrodes 30 illustrated in FIG. 1A, the electrodescomprise at least one parenchymal electrode 30, which is implanted inparenchyma 50 of brain 52, e.g., using surgical techniques similar tothose used for implantation of electrodes for deep brain stimulation.Alternatively, parenchymal electrode 30 is implanted elsewhere in thesubject in electrical contact with brain parenchyma 50, such as on andin contact with an outer surface of brain 52, as shown for the middleparenchymal electrode 30 illustrated in FIG. 1A. Alternatively oradditionally, for some applications, the electrodes comprise at leastone CSF electrode 32, which is implanted in a CSF-filled space of thebrain, such as ventricular system 54 of brain 52 or a subarachnoid space144 (labeled in FIGS. 4A-G) (e.g., cisterns of subarachnoid space 144).For example, CSF electrode 32 may be implanted using techniques knownfor implanting hydrocephalus shunts, mutatis mutandis. As used in thepresent application, including in the claims, ventricular system 54includes and is limited to lateral ventricles 55 (left and right lateralventricles 55A and 55B), a third ventricle 56, a fourth ventricle 57, acerebral aqueduct 59 (labeled in FIGS. 4A-G), interventricular foramina,a median aperture, and left and right lateral apertures.

For some applications, control circuitry 34 is activated, in addition toconfiguring the electrical current to enhance microglial cell activationfor taking up the substance, to drive parenchymal and CSF electrodes 30and 32 to clear the substance from brain parenchyma 50 to outside brainparenchyma 50, such as into the CSF-filled space, such as ventricularsystem 54 or subarachnoid space 144. More generally, in someapplications control circuitry 34 is activated to drive at least a firstsubset of the electrodes to apply an electrical current to the brain andto configure the electrical current to enhance the microglial cellactivation, and to drive at least a second subset of the electrodes(either the same, distinct, or overlapping with the first subset) toapply an electrical current and to configure the current to enhanceclearance of the substance from brain parenchyma 50 to outside brainparenchyma 50. For some applications, the substance comprises amyloidbeta, metal ions, a tau protein, and/or a waste substance. As used inthe present application, including in the claims, clearing a substancefrom the brain parenchyma is to be understood as including clearing aportion of the substance, without clearing all of the substance.Typically, in order to clear the substance from brain parenchyma 50 tooutside brain parenchyma 50, control circuitry 34 applies a voltage or acurrent between parenchymal and CSF electrodes 30 and 32 (i.e., controlcircuitry 34 regulates the voltage or the current).

For some applications, control circuitry 34 is activated to driveparenchymal and CSF electrodes 30 and 32 to apply the electrical currentto enhance the microglial cell activation, optionally in addition toclearing the substance from brain parenchyma 50 to outside brainparenchyma 50, such as into the CSF-filled space.

Typically, a healthcare worker, such as a physician, activates controlcircuitry 34 to provide the functions described herein. Activating thecontrol unit may include configuring parameters and/or functions of thecontrol circuitry (such as using a separate programmer or externalcontroller), or activating the control unit to perform functionspre-programmed in the control circuitry. Control circuitry 34 typicallycomprises appropriate memory, processor(s), and hardware runningsoftware that is configured to provide the functionality of controlcircuitry described herein.

For some applications, control circuitry 34 is activated to (a)configure the electrical current to enhance the microglial cellactivation with a first duty cycle during a treatment period having aduration of at least one hour, and (b) configure the electrical currentto enhance the clearance of the substance from brain parenchyma 50 tooutside brain parenchyma 50 with a second duty cycle during thetreatment period, the second duty cycle greater than the first dutycycle. For some applications, control circuitry 34 is activated to (a)configure the electrical current to enhance the microglial cellactivation intermittently during the treatment period, and (b) configurethe electrical current to enhance the clearance of the substance frombrain parenchyma 50 to outside brain parenchyma 50 generallycontinuously during the treatment period.

For some applications, control circuitry 34 is activated to configurethe electrical current to enhance the microglial cell activation duringactivation periods alternating with rest periods. Typically, the restperiods have an average duration greater than one hour, such as at least12 hours, at least 24 hours, at least 30 hours, at least 72 hours, atleast one week, or at least one month. For example, control circuitry 34may be activated to provide relatively long rest periods between theactivations periods. For some applications, the activation periods havean average duration of less than one hour.

For some applications, control circuitry 34 is activated to (a)configure the electrical current to enhance the microglial cellactivation by configuring the electrical current as alternating current,and (b) configure the electrical current to enhance clearance of thesubstance from brain parenchyma 50 to outside brain parenchyma 50 byconfiguring the electrical current as direct current. Alternatively, forsome applications, control circuitry 34 is activated to (a) configurethe electrical current to enhance the microglial cell activation byconfiguring the electrical current as direct current, and (b) configurethe electrical current to enhance clearance of the substance from brainparenchyma 50 to outside brain parenchyma 50 by configuring theelectrical current as direct current.

For some applications in which control circuitry 34 is activated todrive parenchymal and CSF electrodes 30 and 32, current may flowgenerally through tissue that is located between parenchymal and CSFelectrodes 30 and 32. Alternatively or additionally, at least a portionof the current may flow between (a) parenchymal electrode 30 and (b) anarea of the CSF-filled space (e.g., ventricular system 54) nearestparenchymal electrode 30. The inventors have appreciated that because ofthe low electrical resistance of cerebrospinal fluid (CSF) in theCSF-filled space, such as ventricular system 54, the ventricles are tosome extent a single entity electrically. Therefore, a large portion ofthe current flows to the nearest portion of ventricular system 54, evenif CSF electrode 32 is implanted in a ventricle remote from parenchymalelectrode 30. For example, as shown in FIG. 1B, if a parenchymalelectrode 30A is implanted in a right hemisphere of brain 52, most ofthe current may flow between parenchymal electrode 30A and an area 58 ofright ventricle 55B nearest parenchymal electrode 30A, even though CSFelectrode 32 is implanted in left ventricle 55A.

For some applications in which control circuitry 34 is activated todrive parenchymal and CSF electrodes 30 and 32 to clear the substancefrom brain parenchyma 50 into the CSF-filled space, the voltage appliedbetween the electrodes may clear the substance electrophoretically,because of a positive or negative charged interface between the surfaceof the particles of the substance and the surrounding brain tissuefluids. For these applications, the voltage applied between theelectrodes causes a potential difference between brain parenchyma 50 andthe CSF-filled space, such as ventricular system 54, which causesmovement of the substance from brain parenchyma 50 to the CSF-filledspace, such as ventricular system 54. Alternatively or additionally, forsome applications, the voltage applied between the electrodes may clearthe substance electroosmotically, because of a positive or negativecharge of fluid in the parenchyma. For these applications, the voltageapplied between the electrodes causes a potential difference betweenbrain parenchyma 50 and the CSF-filled space, such as ventricular system54, which causes increased flow from brain parenchyma 50 to theCSF-filled space, such as ventricular system 54, and thus increasedtransport of the substance from parenchyma 50 to the CSF-filled space,such as ventricular system 54.

For some applications, system 20 comprises a plurality of parenchymalelectrodes 30 and/or a plurality of CSF electrodes 32. Parenchymalelectrodes 30 may be implanted in one or both hemispheres of brain 52,and/or at one or more than one location in each of the hemispheres. Forsome applications, such as shown in FIGS. 1A-C, system 20 comprises aplurality of parenchymal electrodes 30 and exactly one CSF electrode 32.For example, the single CSF electrode 32 may be implanted in one oflateral ventricles 55 or third ventricle 56, which, as discussed above,are to a large degree in good electrical connectivity with the otherventricles. For other applications (configuration not shown), system 20comprises (a) exactly two CSF electrodes 32, which are implanted in leftand right lateral ventricles 55A and 55B, respectively, or (b) exactlythree CSF electrodes 32, which are implanted in left and right lateralventricles 55A and 55B and third ventricle 56, respectively.

For applications in which system 20 comprises a plurality of parenchymalelectrodes 30 and/or a plurality of CSF electrodes 32, system 20typically comprises a corresponding plurality of parenchymal electrodeleads 36 and/or a corresponding plurality of CSF electrode leads 38.Each of the leads may comprise separate electrical insulation, and/or aportion of the leads may be joined and share common electricalinsulation, as shown in FIGS. 1A-C for parenchymal electrode leads 36.Control circuitry 34 may be activated to independently drive parenchymalelectrodes 30, e.g., using separately circuitry. Alternatively, one ormore of parenchymal electrodes 30 may be shorted to one another, suchthat the control circuitry drives the shorted electrodes together.Control circuitry 34 may be activated to drive parenchymal electrodes 30simultaneously or at different times.

For some applications, brain parenchyma 50 in which parenchymalelectrode 30 is implanted comprises white matter of the brain.

As used in the present application, including the claims, “treating”includes both treating a subject already diagnosed with Alzheimer'sdisease and/or CAA (such as by delaying, slowing, or reversingprogression of the disease, e.g., in a patient diagnosed at an earlystage), as well as preventing the development of Alzheimer's diseaseand/or CAA in a subject not diagnosed with the disease and/orasymptomatic for the disease. For example, the techniques describedherein may be used to prevent or delay the development of Alzheimer'sdisease and/or CAA in responsive to detection of an abnormal level ofamyloid beta, such as using a blood test or a spinal tap.

For some applications, control circuitry 34 is configured to beimplanted subcutaneously, such under skin of the skull of the subject ifthe housing containing the control circuitry is small, or elsewhere inthe subject's body, such as in the upper chest, if the housing of thecontrol circuitry is larger (e.g., includes batteries), with leadsthrough the neck, or optionally in the head. For these applications,control circuitry 34 is typically driven by an external controller thatis in wireless or wired communication with control circuitry 34. Forsome applications, the external controller is mounted on a bed of thesubject (e.g., disposed within a mattress), and is configured toactivate control circuitry 34 only at night, and/or only when thesubject is sleeping. Such nighttime activation may to some degree mimicthe natural timing of clearance of the substance (e.g., amyloid beta ortau protein) during sleep, during which the extracellular spaces arewider than during wakefulness, which allows more interstitial fluid(ISF) flow within the brain. For other applications, control circuitry34 is configured to be disposed externally to the subject.

For some applications in which control circuitry 34 is activated todrive parenchymal and CSF electrodes 30 and 32, control circuitry 34 isactivated to drive parenchymal and CSF electrodes 30 and 32 to clear thesubstance by applying a non-excitatory current between parenchymal andCSF electrodes 30 and 32, i.e., the current does not cause propagationof action potentials. Thus, in these applications, control circuitry 34is activated to set parameters of the current such that the current doesnot affect, or only minimally affects, neuronal activity. Alternatively,the applied current does excite brain tissue, such as to a small extent.

For some applications in which control circuitry 34 is activated todrive parenchymal and CSF electrodes 30 and 32 to clear the substancefrom brain parenchyma 50 into the CSF-filled space, control circuitry 34is activated to drive parenchymal and CSF electrodes 30 and 32 to clearthe substance by applying direct current (DC) between parenchymal andCSF electrodes 30 and 32. As used in the present application, includingin the claims, direct current means a current having a constantpolarity; the amplitude of the direct current may or may not vary overtime, and may sometimes be zero. For some applications in which controlcircuitry 34 is activated to drive parenchymal and CSF electrodes 30 and32 to enhance the activation of microglial cells, control circuitry 34is activated to drive parenchymal and CSF electrodes 30 and 32 to applydirect current (DC) between parenchymal and CSF electrodes 30 and 32.

For some applications in which control circuitry 34 is activated todrive parenchymal and CSF electrodes 30 and 32, control circuitry 34 isactivated to apply the direct current with an average amplitude of atleast 1 mA, no more than 5 mA, and/or between 1 and 5 mA. Alternativelyor additionally, for some applications, control circuitry 34 isactivated to apply the direct current with an average amplitude of lessthan 1.2 V (such an amplitude may avoid electrolysis in the vicinity ofone or both of the electrodes).

For some applications in which control circuitry 34 is activated todrive parenchymal and CSF electrodes 30 and 32 to clear the substancefrom brain parenchyma 50 into the CSF-filled space, such as when thesubstance is amyloid beta, control circuitry 34 is activated toconfigure parenchymal electrode 30 to be a cathode, and CSF electrode 32to be an anode. Alternatively, control circuitry 34 is activated toconfigure parenchymal electrode 30 to be an anode, and CSF electrode 32to be a cathode. For applications in which the voltage applied betweenthe electrodes clears the substance electrophoretically, the selectedpolarity of the electrodes typically depends on whether the substancehas a positive or negative effective charge. Similarly, for applicationsin which the voltage applied between the electrodes clears the substanceelectroosmotically, the selected polarity of the electrodes typicallydepends on whether the fluid has a positive or negative effectivecharge.

For some applications in which control circuitry 34 is activated todrive parenchymal and CSF electrodes 30 and 32, control circuitry 34 isactivated to apply the direct current as a series of pulses. For someapplications, the series of pulses has an average pulse duration of atleast 10 milliseconds, no more than 300 seconds, and/or between 10milliseconds and 300 seconds, such as: (a) at least 10 milliseconds, nomore than 100 milliseconds, and/or between 10 and 100 milliseconds, (b)at least 100 milliseconds, no more than 300 seconds (e.g., no more than500 milliseconds), and/or between 100 and 300 seconds (e.g., between 100and 500 milliseconds). (c) at least 500 milliseconds, no more than 5seconds, and/or between 500 milliseconds and 5 seconds, (d) at least 5seconds, no more than 10 seconds, and/or between 5 and 10 seconds, or(e) at least 10 seconds, no more than 100 seconds, and/or between 10 and100 seconds. For some applications, the pulses are applied at afrequency of at least 0.001 Hz, no more than 1 kHz. and/or between 0.001and 1 kHz, such as: (a) at least 100 Hz, no more than 1 kHz, and/orbetween 100 Hz and 1 kHz, (b) at least 20 Hz, no more than 100 Hz,and/or between 20 and 100 Hz, (c) at least 10 Hz, no more than 90 Hz.and/or between 10 and 90 Hz (e.g., at least 30 Hz, no more than 50 Hz.and/or between 30 Hz and 50 Hz, e.g., 40 Hz) or (d) at least 1 Hz, nomore than 10 Hz, and/or between 1 and 10 Hz. Alternatively oradditionally, for some applications, the series of pulses has a dutycycle of at least 1%, no more than 50%, and/or between 1% and 50%, suchas: (a) at least 1%, no more than 5%, and/or between 1% and 5%, (b) atleast 5%, no more than 10%, and/or between 5% and 10%, (c) at least 10%,no more than 25%, and/or between 10% and 25%, or (d) at least 25%, nomore than 50%, and/or between 25% and 50%. Typically, but notnecessarily, the duty cycle is no more than 90%, because a given levelof applied voltage produces higher current in the tissue if thecapacitance in the tissue is allowed to discharge between pulses.

For some of the applications in which control circuitry 34 applies avoltage between parenchymal and CSF electrodes 30 and 32 in a series ofDC pulses, the resulting current decays because of the effects of tissueelectrolytes. The current may decay by about two-thirds of its initialmagnitude within tens of milliseconds after commencement of applicationof each pulse. In order to overcome this capacitance effect, controlcircuitry 34 is activated to apply the voltage intermittently, in orderto provide time periods between pulses during which the capacitancedischarges.

For some applications in which control circuitry 34 is activated todrive parenchymal and CSF electrodes 30 and 32, control circuitry 34 isactivated to apply the voltage intermittently with a preprogrammedfrequency and/or duty cycle. These parameters may be (a) applicable toall patients or a subgroup of patients, (b) set during a calibrationprocedure upon implantation of the electrodes, or (c) set based on ageometry of placement of parenchymal and/or CSF electrodes 30 and/or 32.Alternatively, control circuitry 34 is configured to set theseparameters in real time by sensing the current resulting from theapplied voltage.

For some applications in which control circuitry 34 is activated todrive parenchymal and CSF electrodes 30 and 32, control circuitry 34 isactivated to measure the current resulting from the applied voltageduring each of the applied pulses, and to terminate each of the appliedpulses when the magnitude of the measured current falls below athreshold value. For example, the threshold value may be a preprogrammedconstant, or may be based on (e.g., a percentage of) the initial currentmagnitude measured upon commencement of the respective pulse. Controlcircuitry 34 waits during a discharge period before applying the nextpulse.

For some applications in which control circuitry 34 is activated todrive parenchymal and CSF electrodes 30 and 32 to clear the substancefrom brain parenchyma 50 into the CSF-filled space, control circuitry 34is activated to apply, between parenchymal and CSF electrodes 30 and 32,alternating current (AC) in:

-   -   a primary subset of the pulses at a primary polarity selected to        electrophoretically and/or electroosmotically clear the        substance, at a primary voltage and with a primary average pulse        duration, and    -   a secondary subset of the pulses at a secondary polarity        opposite the primary polarity, at a secondary voltage less than        the primary voltage, and with a secondary average pulse duration        greater than the primary average pulse duration.

Because of the lower secondary voltage, the secondary subset of thepulses to a large extent does not reverse the clearance of the substanceachieved during application of the primary subset of the pulses. Thistechnique may also help avoid electrolysis in the vicinity of one orboth of the electrodes, even if the primary voltage is higher than athreshold DC voltage (e.g., 1.2 V) that might otherwise causeelectrolysis.

For some applications in which control circuitry 34 is activated todrive parenchymal and CSF electrodes 30 and 32 to clear the substancefrom brain parenchyma 50 into the CSF-filled space, such as illustratedin FIG. 1C, parenchymal and CSF electrodes 30 and 32 are implanted suchthat one or more areas of build-up 64 of the substance in brainparenchyma 50 is between the electrodes, rather than implantingparenchymal electrode 30 within the area of build-up. For example, thearea(s) of build-up may include amyloid plaque and/or tauprotein-related nerve tissue tangles. To this end, typically the area ofbuild-up is first identified, for example by performing imaging of brain52, such as MRI (e.g., functional MRI (fMRI)) or PET imaging of brain52. As mentioned above, a plurality of parenchymal electrodes 30 and/ora plurality of CSF electrodes 32 may be implanted, such as if there ismore than one area of build-up 64 of the substance.

For some applications in which control circuitry 34 is activated todrive parenchymal and CSF electrodes 30 and 32 to clear the substancefrom brain parenchyma 50 into the CSF-filled space, also such asillustrated in FIG. 1C, the one or more parenchymal electrode areimplanted such that the one or more areas of build-up 64 are betweenparenchymal electrode 30A and respective areas 80 of the CSF-filledspace, such as ventricular system 54, nearest areas of build-up 64. CSFelectrode 32 may or may not be implanted near areas 80. For applicationsin which CSF electrode 32 is not implanted near areas 80, the substanceof area of build-up 64 may still be driven into nearest areas 80 of theCSF-filled space, such as ventricular system 54, because nearest areas80 are in fluid communication with CSF electrode 32 via CSF of theCSF-filled space, such as ventricular system 54, as discussed above. Asmentioned above, a plurality of parenchymal electrodes 30 and/or aplurality of CSF electrodes 32 may be implanted, such as if there ismore than one area of build-up 64 of the substance, or in general inorder to provide good clearance of the substance.

For some applications, parenchymal electrode 30 is further used forapplying deep brain stimulation, as is known in the art. For example,the deep brain stimulation may be applied when the electrodes are notbeing driven to enhance the activation of the microglial cells or todrive the substance into the CSF-filled space, such as the ventricularsystem. As is known in the art, the deep brain stimulation may beapplied to reduce tremor and block involuntary movements in patientswith motion disorders, such as Parkinson's disease, or to treatepilepsy, cluster headaches, Tourette syndrome, chronic pain, or majordepression. The implantation location of parenchymal electrode 30 may beselected to be appropriate for the treatment of a particular condition,as well as for clearing the substance.

For some applications, control circuitry 34 is activated to drive theelectrodes to enhance the activation of the microglial cells insessions, each of which has a duration of several seconds or severalminutes, or continuously for longer periods (e.g., 30 minutes). For someapplications, the electrodes are not driven for a period that is atleast an hour. Optionally, control circuitry 34 is activated to drivethe electrodes only when the subject is sleeping, such as to takeadvantage of the widening of extracellular spaces and/or to inhibit anysensations that may be associated with the driving. For example, controlcircuitry 34 may be activated to use one or more of the electrodes asEEG electrodes to detect sleep. For some applications, power foractivating and/or charging control circuitry 34 is transmitted from awireless energy transmitter in a device applied to the head, such as ahat, or from a wireless energy transmitter in, under, or above amattress, such as described hereinabove. For some applications, controlcircuitry 34 is activated to drive the electrodes according to apre-selected schedule, such as a duty cycle, such as for a few hours perday. For example, control circuitry 34 may be configured to becontrolled and/or powered by an extracorporeal control circuitry, suchas a control circuitry comprising a wireless transmitter, disposed inand/or in the vicinity of the subject's bed. For some applications, oneor more rest periods during which the control circuitry does not drivethe electrodes are provided in the pre-selected schedule.

For any of the applications described herein, CSF electrode 32 may beimplanted in one of the following sites, rather than in ventricularsystem 54:

-   -   a central canal of the spinal cord (which is in fluid        communication with ventricular system 54); or    -   a subarachnoid space 144 (labeled in FIGS. 4A-G) (which is in        fluid communication with ventricular system 54 because CSF        drains into cisterns of subarachnoid space 144 via foramina of        ventricular system 54).

For some applications, instead of implanting CSF electrode 32 inventricular system 54, an electrode is implanted in superior sagittalsinus 142 (labeled in FIGS. 4A-G).

For any of the applications described herein, parenchymal electrode 30may be implanted in superior sagittal sinus 142, rather than in brainparenchyma 50 (typically, in these applications, CSF electrode 32 isimplanted in ventricular system 54).

Reference is again made to FIGS. 1A-C. For some applications, controlcircuitry 34 is configured to detect a voltage difference betweenparenchyma 50 and the CSF-filled space, and set a level of the voltageapplied between parenchymal and cerebrospinal fluid (CSF) electrodes 30and 32 responsively to the detected voltage difference.

Reference is now made to FIGS. 2A-B, which are schematic illustrationsof cross-sections of a rat brain showing results of an animal experimentperformed in accordance with an application of the present invention. Arat was anesthetized, a first electrode 130 (a piece of Pt—Ir wiresoldered to a miniature connector) was inserted through a hole into thesagittal sinus, and a second electrode 132 (a pieces of Pt—Ir wiresoldered to a small electronic connector) was inserted through a hole indura mater into the right lateral ventricle.

As shown in FIG. 2A, bromephenol blue dye was stereotaxically deliveredinto both hemispheres of the rat brain at designated coordinates 120 and122. By using the left hemisphere as a diffusion control, thisexperimental setup allowed pairwise comparisons within the same animal,thereby ruling out any other effects that might effect a directedmigration of the dye in the brain.

Control circuitry was activated to apply a constant-polarity (DC)current to only the right hemisphere, between first and secondelectrodes 130 and 132, configuring first electrode 130 as a cathode andsecond electrode 132 as an anode, because bromephenol blue dye compriseseffectively anionic (negatively-charged) molecules. The current wasapplied by repeatedly alternating between two modes: (a) a first mode,in which the current was applied continuously for 5 minutes at amagnitude of 1-2 mA, and (b) a second mode, in which the current wasapplied in 10-ms-duration pulses, one pulse per second (i.e., a pulsefrequency of 1 Hz), at a magnitude of 1-2 mA.

FIG. 2B shows the displacement of the bromephenol blue dye afterapplication of the current to the right hemisphere. As can be seen, thebromephenol blue dye in the left hemisphere experienced minimaldispersion and no directed displacement. In contrast, in the righthemisphere, the applied current moved the bromephenol blue dye towardthe lateral ventricle. The dye moved with the average velocity of0.28+/−0.006 mm/min, which was more than 14 times greater than theobserved diffusion rate in the left hemisphere. In the right hemisphere,the linear displacement of the dye profile center was about 1.9±0.08 mm,while the front of the dye profile reached a maximum distance of about2.81±0.07 mm from the center of the injection point.

The results of this experiment demonstrated that molecules of dye can bemoved within brain tissue by applying a DC current using two electrodesimplanted in the brain, and that in such a setup, a natural migrationpath is toward the ventricles. The inventors believe that application ofthe current between the electrodes may have moved the dyeelectrophoretically. The inventors also believe that implantation of thefirst electrode directly in brain parenchyma, rather than in thesuperior sagittal sinus, may provide even better current-driven movementof molecules, because the resistance of the parenchyma-sinus interfacewas calculated as more than two-fold higher than the resistance measuredwithin the parenchyma, based on data collected during the experiment.

Amyloid Beta Mobility and Directionality Assessment

Reference is now made to FIG. 3, which is a graph showing results of anin vitro experiment performed in accordance with an application of thepresent invention. The experiment assessed the extent to whichapplication of direct current (DC) eliminated amyloid beta peptides froman artificial cerebrospinal fluid (aCSF) solution (comprising phosphatebuffered saline (PBS) solution). Pt—Ir electrodes were inserted into acompartment filled with the aCSF solution. Fluorophore-tagged amyloidbeta peptides were dissolved to three different dilution levels (2:500,5:500, and 10:500). Constant DC currents of three different durations(5, 10, and 15 minutes) were applied from a 1.5 V alkaline battery tothe aCSF solution containing the fluorophore-tagged amyloid betapeptides. The directionality and overall capability of amyloid beta toundergo electrophoretic movement was assessed by densitometric analysisof fluorescence on each electrode.

The fluorescence intensity was measured at both electrodes, and thefluorescence intensity was normalized at the positively-chargedelectrode (anode) with respect to the negatively-charged electrode(cathode) by taking the ratio of fluorescence. Data was averaged fromall the measurements and is presented as mean and standard error of meanin FIG. 3.

As can be seen in FIG. 3, current-duration-dependent enhancement offluorescence was observed near the positively-charged electrode (anode)(for the 2:500 dilution level). The difference in fluorescence betweenthe anodes and the cathodes was statistically significant (one tailedt-test: p<10{circumflex over ( )}−15; t=12.17) for thecurrent-duration-dependent analysis. The current-duration-dependenttrend of fluorescence enhancement on the positively-charged electrodewas also statistically significant for 15-minute current application vs.5- and 10-minute current application (one-way ANOVA: p<0.001, F=8.92;Holm-Sidak post-hoc analysis: p<0.01, t=3.37 for 15 minutes vs. 5minutes and t=3.889 for 15 minutes vs. 10 minutes due to nonspecificbinding). At all concentrations there was significant attraction of theamyloid beta to the anode vs. the cathode.

These experimental results demonstrate that soluble monomeric amyloidbeta in its native conformation is negatively charged in aCSF and iscapable of moving in the electrical field without the need to add anyamphiphilic detergents to provide the negative charge to the amyloidbeta.

Amyloid Beta Electrophoretic Mobility Assessment in Wild Type MouseBrain Parenchyma

An animal experiment was performed in accordance with an application ofthe present invention. 20 three-month wild-type mice were anesthetized,and soluble fluorophore-tagged amyloid beta (1-42), HiLyte™ Fluor488-labeled, Human (AnaSpec, USA) was injected into the brain parenchyma(AP=−2, ML=0.84, DV=1.2). A first Pt—Ir electrode was implanted in brainparenchyma (AP=−2.8, ML=0.84, DV=1.5), and a second Pt—Ir electrode wasimplanted in the lateral ventricle (AP=−0.5, ML=0.84, DV=1.6). Anelectrical field generated by the current between the electrodes coveredthe amyloid beta injection focus. The current application was applied bythe repetition of single pulses. The following parameters were used:voltage: 70 V; and frequency: 1 Hz. The current application protocol wasas follows: (a) 15 minutes with a pulse duration of 1 ms; (b) 15 minuteswith a pulse duration of 10 ms; and (c) 15 minutes with a pulse durationof 100 ms. The frequency was kept constant but the duty cycle wasincreased.

Assessment of amyloid beta movement directionality in the electricalfield was conducted by using antibodies directed against 1-16 amino acidstrip of 6E10 (Catalog no. SIG-39320) to visualize the traces of amyloidbeta peptide movement in the electrical field. Tissue structure and cellnuclei were visualized by DAPI staining and microglial cells (Iba1).Amyloid beta movement trajectory was evaluated at differentmagnifications (4× and 10×). Sagittal slices were stained withantibodies against cell nuclei (blue), amyloid beta (6E10, green), andmicroglial cells (Iba1, red), and imaged by fluorescence microscopy.

Amyloid beta movement was visualized in mouse brains to which theelectrical current was applied. The electrode inserted into the lateralventricle was positively charged, and, similarly to the in vitroexperiment described hereinabove with reference to FIG. 3, the appliedcurrent was capable of inducing amyloid beta movement. In addition, theapplied current enhanced activation of microglial cells, as describedhereinbelow.

These experimental results demonstrate that electrophoretic movement ofamyloid beta peptides is possible in the brain parenchyma with theelectrical current-application protocol used in the experiment. Thedirectionality of amyloid beta peptide movement was similar to thatobserved the in vitro experiment described hereinabove with reference toFIG. 3. The inventors hypothesize that electrical-current-basedelimination of amyloid beta is a slow process inducing additionalbiological phenomena, perhaps including increased microglial activationin the neuroprotective (M2) phenotype, which may help clear amyloid betafrom the brain parenchyma.

Another animal experiment was performed in accordance with anapplication of the present invention, to assess the effect ofapplication of current on elimination of the fibrillary form of amyloidbeta in a 5×FAD mice model of Alzheimer's disease, without the injectionof the soluble form of amyloid beta (i.e., unlike in the animalexperiment described immediately above). 4-month 5×FAD mice wereanesthetized. A first Pt—Ir electrode was implanted brain parenchyma(AP=−2.8, ML=0.84, DV=1.5), and a second Pt—Ir electrode was implantedin the lateral ventricle (AP=−0.5, ML=0.84, DV=1.6). The currentapplication was applied by the repetition of single pulses. Thefollowing parameters were used: voltage: 70 V; and frequency: 1 Hz. Thecurrent application protocol was as follows: (a) 15 minutes with a pulseduration of 1 ms; (b) 15 minutes with a pulse duration of 10 ms; and (c)15 minutes with a pulse duration of 100 ms. The frequency was keptconstant but the duty cycle was increased.

Reduction of amyloid plaque density was evaluated by immunohistochemicalanalysis. Application of electrical current markedly enhancedco-localization of amyloid beta peptides and microglial cell markers.Sagittal slices from the 5×FAD were stained with antibodies against cellnuclei (blue), amyloid beta (6E10, green), and microglial cells (IbaI,red), and imaged by fluorescence microscopy. These experimental resultsdemonstrate that application of electrical current enhances the nativebrain cleaning mechanism of microglial cells, such as by phagocytosis.

Reference is made to FIGS. 4A-G, which are schematic illustrations ofalternative configurations of system 20, in accordance with respectiveapplications of the present invention. These figures show an anteriorview of brain 52. For some applications, at least one of the electrodesdescribed hereinabove with reference to FIGS. 1A-C for enhancingactivation of microglial cells is positioned outside and in electricalcontact with skull 168, e.g., under skin 176 of head 174. For example,the at least electrode may comprise a midplane treatment electrode 150,such as described hereinbelow. Alternatively or additionally, for someapplications, at least one of the electrodes described hereinabove withreference to FIGS. 1A-C for enhancing activation of microglial cells ispositioned on an external surface of skin 176 of head 174, such asdescribed hereinbelow with reference to FIG. 4E regarding midplanetreatment electrodes 150; the at least one of the electrodes forenhancing activation of microglial cells is not necessarily a midplanetreatment electrode 150 and may alternatively be positioned elsewhere onthe external surface of skin 176 of head 174.

In some of these applications, system 20 is configured to, in additionto clearing the substance (e.g., the amyloid beta, the metal ions, thetau protein, and/or the waste substance) from brain parenchyma 50 intothe CSF-filled space, to clear the substance from the CSF-filled space(e.g., subarachnoid space 144) to superior sagittal sinus 142. Thesetechniques may be used in combination with any of the techniquesdescribed hereinabove. For some of these techniques, control circuitry34 is configured to apply the treatment current as direct current.

For some applications described with reference to FIGS. 4A-G, controlcircuitry 34 is configured to simultaneously drive electrodes to both(a) clear the substance from brain parenchyma 50 into the CSF-filledspace, and (b) clear the substance from the CSF-filled space to superiorsagittal sinus 142. For example, control circuitry 34 may be configuredto apply different respective voltages to parenchymal electrode 30, CSFelectrode 32, and a midplane treatment electrode 150, described below.For example, control circuitry 34 may be configured to apply first,second, and third voltages to parenchymal electrode 30, CSF electrode32, and midplane treatment electrode 150, respectively, the thirdvoltage more positive than the second voltage, which is in turn morepositive than first voltage. The total potential difference between thefirst and the third voltages is typically no greater than 1.2 V volt toavoid electrolysis in the vicinity of one or both of the electrodes.

For other applications described with reference to FIGS. 4A-G, controlcircuitry 34 is configured to alternatingly drive sets of theelectrodes, such as (a) during a plurality of first time periods,driving parenchymal electrode 30 and CSF electrode 32, in order to clearthe substance from brain parenchyma 50 into the CSF-filled space, and(b) during a plurality of second time periods, typically not overlappingwith the first time periods, driving midplane treatment electrode 150and either CSF electrode 32 or another electrode (described below), inorder to clear the substance from the CSF-filled space to superiorsagittal sinus 142.

For some applications described with reference to FIGS. 4A-G, controlcircuitry 34 is configured to clear the substance to superior sagittalsinus 142 by electroosmotically driving fluid from the CSF-filled space(e.g., subarachnoid space 144) to superior sagittal sinus 142. For someapplications, control circuitry 34 is configured to drive the fluid fromthe CSF-filled space of the brain to superior sagittal sinus 142 byconfiguring midplane treatment electrode 150 as a cathode, and CSFelectrode 32 as an anode.

For some applications described with reference to FIGS. 4A-G, controlcircuitry 34 is configured to clear the substance by electrophoreticallydriving the substance from the CSF-filled space (e.g., subarachnoidspace 144) to superior sagittal sinus 142. For some applications,application of the treatment current causes a potential differencebetween the CSF-filled space and superior sagittal sinus 142, whichcauses movement of the substance from the CSF-filled space to superiorsagittal sinus 142.

For some applications, such as shown in FIG. 4A, parenchymal electrode30 is implanted in brain parenchyma 50, and CSF electrode 32 isimplanted in the CSF-filled space, such as ventricular system 54 orsubarachnoid space 144. A midplane treatment electrode 150 is disposedeither (a) in superior sagittal sinus 142 (as shown in FIG. 4A), or (b)over superior sagittal sinus 142 (configuration not shown in FIG. 4A,but shown in FIGS. 4B-G). A second CSF electrode 152 is implanted theCSF-filled space, such as ventricular system 54 (configuration not shownin FIG. 4A) or subarachnoid space 144 (as shown in FIG. 4A). Controlcircuitry 34 is activated to apply (a) a first voltage betweenparenchymal electrode 30 and CSF electrode 32, to clear the substancefrom brain parenchyma 50 into the CSF-filled space, and (b) a secondvoltage between midplane treatment electrode 150 and second CSFelectrode 152, to clear the substance from the CSF-filled space tosuperior sagittal sinus 142. This technique may be used in combinationwith the techniques described hereinbelow with reference to FIGS. 4B-G,mutatis mutandis.

Alternatively, for some applications, such as shown in FIG. 4B,parenchymal electrode 30 is implanted in brain parenchyma 50, and CSFelectrode 32 is implanted in the CSF-filled space, such as ventricularsystem 54 or subarachnoid space 144. Midplane treatment electrode 150 isdisposed either (a) in superior sagittal sinus 142 (as shown in FIG.4A), or (b) over superior sagittal sinus 142 (as shown in FIGS. 4B-G).Control circuitry 34 is activated to apply (a) a first voltage betweenparenchymal electrode 30 and CSF electrode 32, to clear the substancefrom brain parenchyma 50 into the CSF-filled space, and (b) a secondvoltage between CSF electrode 32 and midplane treatment electrode 150,to clear the substance from the CSF-filled space to superior sagittalsinus 142.

For some applications, such as shown in FIGS. 4B-C, midplane treatmentelectrode 150 is adapted to be disposed over superior sagittal sinus142. For some of these applications, midplane treatment electrode 150 isadapted to be disposed under a skull 168 of head 174 of the subject,such as in contact with an outer surface of superior sagittal sinus 142(either under the dura mater or in contact with an outer surface of thedura mater). For others of these applications, midplane treatmentelectrode 150 is adapted to be disposed outside and in electricalcontact with skull 168. As used in the present application, including inthe claims, “over the superior sagittal sinus” means aligned with thesuperior sagittal sinus at a location more superficial than the superiorsagittal sinus, i.e., at a greater distance from a center of the head.In the configurations shown in FIGS. 4B and 4C, control circuitry 34 isconfigured to clear the substance from the CSF-filled space to superiorsagittal sinus 142, by applying a treatment current between midplanetreatment electrode 150 and CSF electrode 32. Alternatively, theplacements of midplane treatment electrode 150 shown in FIGS. 4B and 4Care used in combination with the configuration described hereinabovewith reference to FIG. 4A.

For some applications, such as shown in FIG. 4D, system 20 comprises aplurality of midplane treatment electrodes 150, such as at least 5, nomore than 20, and/or between 5 and 20 midplane treatment electrodes 150.Midplane treatment electrodes 150 are disposed either (a) in superiorsagittal sinus 142 (configuration not shown in FIG. 4D, but shown inFIG. 4A), or (b) over superior sagittal sinus 142 (as shown in FIG. 4D,or in FIG. 4B).

For any of the applications described herein, including, but not limitedto those described with reference to FIGS. 4A-G, CSF electrode 32 may beadapted to be disposed between 1 and 12 cm of a sagittal midplane 164 ofskull 168. For some applications, the method may comprise implanting CSFelectrode 32 between 1 and 12 cm of sagittal midplane 164 of skull 168.

For any of the applications described herein, including, but not limitedto those described with reference to FIGS. 4A-G, the CSF-filled spacemay be subarachnoid space 144, CSF electrode 32 may be a subarachnoidelectrode, configured to be implanted in subarachnoid space 144, andcontrol circuitry 34 may be configured to clear the substance fromsubarachnoid space 144 to superior sagittal sinus 142.

For some applications, such as shown in FIG. 4E-G, system 20 comprises(a) midplane treatment electrodes 150, adapted to be disposed oversuperior sagittal sinus 142, outside and in electrical contact withskull 168, and (b) lateral treatment electrodes 162, adapted to bedisposed at a distance of between 1 and 12 cm of sagittal midplane 164of skull 168 (the distance is measured in a straight line from a closestportion of each treatment electrode to sagittal midplane 164, ratherthan along the curvature of skull 168). Control circuitry 34 isconfigured to clear the substance from subarachnoid space 144 tosuperior sagittal sinus 142, by applying one or more treatment currentsbetween (a) one or more of midplane treatment electrodes 150 and (b) oneor more of lateral treatment electrodes 162 (each of the treatmentcurrents is schematically illustrated in the figures by a plurality ofcurrent lines 190).

For some applications, system 20 comprises as at least 5, no more than40, and/or between 5 and 40 lateral treatment electrodes 162, such asbetween 5 and 20 lateral treatment electrodes 162, or between 10 and 40lateral treatment electrodes. For some applications, the number of eachtype of treatment electrode is determined based on the size of head 174of the subject. For some applications, system 20 comprises twice as manylateral treatment electrodes 162 as midplane treatment electrodes 150.

For some applications, the one or more treatment currents applied usingmidplane treatment electrodes 150 and lateral treatment electrodes 162pass between subarachnoid space 144 and superior sagittal sinus 142, viainferolateral surfaces 170 of superior sagittal sinus 142. For some ofthese applications, at least 40%, e.g., at least 75% or at least 90%, ofthe treatment currents pass between subarachnoid space 144 and superiorsagittal sinus 142, via inferolateral surfaces 170 of superior sagittalsinus 142. For the applications described immediately above, thelocations of midplane treatment electrodes 150 and/or lateral treatmentelectrodes 162 are typically selected such that the one or moretreatment currents pass through inferolateral surfaces 170. For example,for configurations in which lateral treatment electrodes 162 aredisposed outside and in electrical contact with skull 168, such asdescribed with reference to FIGS. 4C-G, lateral treatment electrodes 162may be disposed at a distance of least 4 cm, no more than 12 cm, and/orbetween 4 and 12 cm of sagittal midplane 164 of skull 168; forconfigurations in which lateral treatment electrodes 162 are implantedunder an arachnoid mater 172 of the subject, such as described withreference to FIGS. 4C-G, lateral treatment electrodes 162 may bedisposed at least 1 cm, no more than 3 cm, and/or between 1 and 3 cm ofsagittal midplane 164 of skull 168.

For some applications, at least five midplane treatment electrodes 150are disposed over superior sagittal sinus 142. Alternatively oradditionally, for some applications, at least five lateral treatmentelectrodes 162 between 1 and 12 cm of sagittal midplane 164 of skull168. For some applications, each of lateral treatment electrodes 162 isdisposed between 1 and 12 cm of at least one of midplane treatmentelectrodes 150.

For some applications, midplane treatment electrodes 150 are disposedwithin 10 mm of sagittal midplane 164 of skull 168. Alternatively oradditionally, for some applications, midplane treatment electrodes 150are disposed such that at least one of midplane treatment electrodes 150is at least 5 mm from another one of midplane treatment electrodes 150,no more than 20 mm from another one of midplane treatment electrodes150, and/or between 5 and 150 mm from another one of midplane treatmentelectrodes 150. For some applications, at least one of lateral treatmentelectrodes 162 is disposed is at least 5 mm from another one of lateraltreatment electrodes 162.

For some applications, such as shown in FIG. 4E, midplane treatmentelectrodes 150 are implanted under skin 176 of head 174. For otherapplications, such as shown in FIG. 4F, midplane treatment electrodes150 are disposed outside head 174, such as on an external surface 178 ofhead 174.

For some applications, system 20 further comprises a midplane lead 180,along which midplane treatment electrodes 150 are disposed (e.g.,fixed). Midplane lead 180 is disposed outside skull 168 in order todispose midplane treatment electrodes 150 over superior sagittal sinus142. For some applications in which midplane treatment electrodes 150are implanted under skin 176, the implantation is performed byintroducing midplane lead 180 through an incision in skin 176, typicallyat a posterior site of the head, and tunneling the midplane lead towardan anterior site of the head, such as near the forehead. Optionally,each of midplane treatment electrodes 150 is inserted through arespective incision in skin 176, and connected to midplane lead 180.

For some applications, such as shown in FIGS. 4E-F, lateral treatmentelectrodes 162 are disposed outside and in electrical contact with skull168. For some of these applications, lateral treatment electrodes 162are implanted under skin 176 of head 174, such as shown in FIG. 4E.Alternatively, lateral treatment electrodes 162 are disposed outsidehead 174, such as on external surface 178 of head 174, such as shown inFIG. 4F. For some of these applications, lateral treatment electrodes162 may be disposed at least 4 cm, no more than 12 cm, and/or between 4and 12 cm of sagittal midplane 164 of skull 168. (As used in the presentapplication, including in the claims, all specified ranges include theirendpoints.) Such positioning may generate one or more treatment currentsthat pass between subarachnoid space 144 and superior sagittal sinus142, via inferolateral surfaces 170 of superior sagittal sinus 142, asdescribed above.

For some applications, system 20 further comprises a lateral lead 182,along which lateral treatment electrodes 162 are disposed (e.g., fixed).Lateral lead 182 is disposed outside skull 168, typically within 1 and12 cm of sagittal midplane 164 of skull 168, in order to dispose lateraltreatment electrodes 162. For some applications in which lateraltreatment electrodes 162 are implanted under skin 176, the implantationis performed by introducing lateral lead 182 through an incision in skin176, typically at a posterior site of the head, and tunneling thelateral lead toward an anterior site of the head, such as near theforehead. Optionally, each of lateral treatment electrodes 162 isinserted through a respective incision in skin 176, and connected tolateral lead 182. For some applications, instead of providing laterallead 182, lateral treatment electrodes 162 are instead coupled tomidplane lead 180. Midplane lead 180 is introduced with the lateralelectrodes constrained, and, the lateral electrodes are configured uponrelease to extend laterally, typically automatically. This configurationmay also be used for applications in which both left and right lateralelectrodes are provided, as described hereinbelow.

For some applications, control circuitry 34 is activated toindependently apply the treatment currents between respective pairs ofmidplane treatment electrodes 150 and lateral treatment electrodes 162.Such independent application of the currents allows continued effectiveoperation of system 20 even if a low resistance should develop betweenthe electrodes of one of the pairs (e.g., because of anatomicalvariations). For some of these applications, in order to enable suchindependent application of the currents, midplane lead 180 comprises aplurality of conductive wires corresponding to a number of midplanetreatment electrodes 150, and lateral lead 182 comprises a plurality ofconductive wires corresponding to a number of lateral treatmentelectrodes 162. Alternatively, control circuitry 34 and the electrodesimplement electrical multiplexing, as is known in the art, in which caseeach of the leads need only comprise a single conductive wire.Alternatively, for some applications, all of midplane treatmentelectrodes 150 are electrically coupled to one another (such as by asingle conductive wire in the midplane lead), and all of lateraltreatment electrodes 162 are electrically coupled to one other (such asby a single conductive wire in the lateral lead).

For some applications of the configuration shown in FIG. 4F, system 20further comprises one or more thin elongate support elements 184, whichcouple lateral leads 182 to midplane lead 180, in order to provideproper spacing and alignment between the midplane electrodes and thelateral electrodes. Support elements 184 are typically non-conductive.

For some applications described with reference to FIGS. 4A-G, controlcircuitry 34 is configured to apply the one or more treatment currentswith an average amplitude of between 1 and 3 milliamps. (The resultingvoltage is typically greater in the configuration shown in FIGS. 4E-Fthan in the configuration shown in FIG. 4G, because the one or moretreatment currents pass through skull 168 twice.)

For some applications described with reference to FIGS. 4A-G, controlcircuitry 34 is activated to apply the one or more treatment currents asdirect current, typically as a plurality of pulses, for example atgreater than 500 Hz and/or less than 2 kHz, e.g., at 1 kHz. For someapplications, a duty cycle of the pulses is above 90%, and for someapplications pulses are not used but instead an effective duty cycle of100% is utilized. Typically, but not necessarily, the duty cycle is 90%or lower, because a given level of applied voltage produces highercurrent in the tissue if the capacitance in the tissue is allowed todischarge between pulses. For other applications, control circuitry 34is activated to apply the one or more treatment currents as alternatingcurrent with a direct current offset and a constant polarity. Forexample, the frequency may be at least 1 Hz, no more than 100 Hz (e.g.,no more than 10 Hz), and/or between 1 Hz and 100 Hz (e.g., between 1 Hzand 10 Hz).

As mentioned above, for some applications, control circuitry 34 isconfigured to clear the substance by electroosmotically driving fluidfrom subarachnoid space 144 to superior sagittal sinus 142. For someapplications, control circuitry 34 is configured to configure midplanetreatment electrodes 150 as cathodes, and lateral treatment electrodes162 as anodes. Alternatively or additionally, increased flow ofcerebrospinal fluid (CSF) out of the brain's ventricular system viasubarachnoid space 144, as a result of the applied voltage, may itselftreat Alzheimer's disease and/or CAA, independent of any directclearance of beta amyloid in the CSF flow.

For some applications, lateral treatment electrodes 162 comprise (a)left lateral treatment electrodes 162A, which are adapted to be disposedleft of sagittal midplane 164 of skull 168, and (b) right lateraltreatment electrodes 162B, which are adapted to be disposed right ofsagittal midplane 164 of skull 168. For some applications, controlcircuitry 34 is configured to configure midplane treatment electrodes150 as cathodes, and left and right lateral treatment electrodes 162Aand 162B as left and right anodes, respectively.

As mentioned above, for some applications, control circuitry 34 isconfigured to clear the substance by electrophoretically driving thesubstance from subarachnoid space 144 to superior sagittal sinus 142.For some applications, lateral treatment electrodes 162 comprise (a)left lateral treatment electrodes 162A, which are adapted to be disposedleft of sagittal midplane 164 of skull 168, and (b) right lateraltreatment electrodes 162B, which are adapted to be disposed right ofsagittal midplane 164 of skull 168. For some of these applications,control circuitry 34 is configured to configure the midplane treatmentelectrodes 150 as anodes, and left and right lateral treatmentelectrodes 162A and 162B as left and right cathodes, respectively. Inexperiments conducted on behalf of the inventor, amyloid beta was foundto be attracted to the positive electrode (anode).

For some applications, lateral treatment electrodes 162 are adapted tobe implanted under an arachnoid mater 172 of the subject, such as inbrain parenchyma 50 (gray or white matter), as shown in FIG. 4G, or insubarachnoid space 144, such as shown in FIG. 4A. For some applications,the same electrodes serve as both parenchymal electrode 30 and lateraltreatment electrodes 162, and are driven by control circuitry 34 eitherat the same time or at different times. For example, lateral treatmentelectrodes 162 may comprise needle electrodes, as is known in the art;optionally, lateral treatment electrodes 162 comprise respectiveproximal anchors 188. This configuration may implement any of thetechniques described hereinabove with reference to FIGS. 4A-F, mutatismutandis.

For some of these applications, lateral treatment electrodes 162 aredisposed at least 1 cm, no more than 3 cm, and/or between 1 and 3 cm ofsagittal midplane 164 of skull 168. Such positioning may generate thetreatment currents that pass between subarachnoid space 144 and superiorsagittal sinus 142, via inferolateral surfaces 170 of superior sagittalsinus 142, as described above. For some applications, each of lateraltreatment electrodes 162 is disposed between 1 and 3 cm of at least oneof midplane treatment electrodes 150. For some applications, each oflateral treatment electrodes 162 is disposed between 1 and 3 cm of oneof midplane treatment electrodes 150 that is closest to the lateraltreatment electrode.

As mentioned above, for some applications, system 20 further comprisesmidplane lead 180, along which midplane treatment electrodes 150 aredisposed (e.g., fixed). Midplane lead 180 is disposed outside skull 168in order to dispose midplane treatment electrodes 150. For some of theseapplications, system 20 further comprises (a) a left lateral lead 182A,along which left lateral treatment electrodes 162A are disposed (e.g.,fixed), and (b) a right lateral lead 182B, along which right lateraltreatment electrodes 162B are disposed (e.g., fixed). Left lateral lead186A is disposed outside skull 168, typically within 1 and 12 cm ofsagittal midplane 164 of skull 168, in order to dispose left lateraltreatment electrodes 162A. Right lateral lead 186B is disposed outsideskull 168, typically within 1 and 12 cm of sagittal midplane 164 ofskull 168, in order to dispose right lateral treatment electrodes 162B.

Reference is again made to 4A-G. For some applications, controlcircuitry 34 is configured to detect a voltage difference betweensubarachnoid space 144 and superior sagittal sinus 142, and set a levelof the one or more treatment currents responsively to the detectedvoltage difference.

Although some of the techniques described hereinabove have beendescribed as treating the subject by electroosmotically driving fluidfrom subarachnoid space 144 to superior sagittal sinus 142, thetechniques may alternatively or additionally be used withoutelectroosmosis.

The scope of the present invention includes embodiments described in thefollowing applications, which are assigned to the assignee of thepresent application and are incorporated herein by reference. In anembodiment, techniques and apparatus described in one or more of thefollowing applications are combined with techniques and apparatusdescribed herein:

-   -   U.S. application Ser. No. 13/872,794, filed Apr. 20, 2013, which        published as US Patent Application Publication 2014/0324128;    -   U.S. application Ser. No. 14/794,739, filed Jul. 8, 2015, which        issued as U.S. Pat. No. 9,616,221;    -   International Application PCT/IL2016/050728, filed Jul. 7, 2016,        which published as PCT Publication WO 2017/006327;    -   U.S. application Ser. No. 14/926,705, filed Oct. 29, 2015, which        issued as U.S. Pat. No. 9,724,515; and    -   International Application PCT/IL2016/051161, filed Oct. 27,        2016, which published as PCT Publication WO 2017/072769.

It will be appreciated by persons skilled in the art that the presentinvention is not limited to what has been particularly shown anddescribed hereinabove. Rather, the scope of the present inventionincludes both combinations and subcombinations of the various featuresdescribed hereinabove, as well as variations and modifications thereofthat are not in the prior art, which would occur to persons skilled inthe art upon reading the foregoing description.

The invention claimed is:
 1. A method comprising: positioning electrodesin or in contact with a head of a subject identified as in need ofenhanced microglial cell activation; and activating control circuitry todrive the electrodes to apply an electrical current to a brain of thesubject in pulses having an average pulse duration of between 0.1 ms and10 ms, and to configure the electrical current to: enhance microglialcell activation for taking up a substance from brain parenchyma with afirst duty cycle during a treatment period having a duration of at leastone hour, and enhance clearance of the substance from brain parenchymato outside the brain parenchyma with a second duty cycle during thetreatment period, wherein the second duty cycle is greater than thefirst duty cycle, wherein the substance is selected from a groupconsisting of: amyloid beta and tau protein, and wherein activating thecontrol circuitry comprises activating the control circuitry to applythe electrical current with an average amplitude of between 0.1 and 5mA, or with an average voltage that results in between 0.1 and 5 mAcurrent.
 2. The method according to claim 1, wherein the substance isamyloid beta, and wherein activating the control circuitry comprisesactivating the control circuitry to configure the electrical current toenhance the microglial cell activation for taking up the amyloid betafrom the brain parenchyma and to enhance the clearance of the betaamyloid from brain parenchyma to outside the brain parenchyma.
 3. Themethod according to claim 1, wherein positioning the electrodescomprises positioning the electrodes in or in contact with the head of asubject identified as at risk of or suffering from Alzheimer's disease.4. The method according to claim 1, wherein positioning the electrodescomprises positioning the electrodes in or in contact with the head of asubject identified as at risk of or suffering from cerebral amyloidangiopathy (CAA).
 5. The method according to claim 1, whereinpositioning the electrodes comprises implanting at least one of theelectrodes intracranially.
 6. The method according to claim 5, whereinimplanting the at least one of the electrodes intracranially comprisesimplanting the at least one of the electrodes in brain parenchyma. 7.The method according to claim 6, wherein the at least one of theelectrodes is a parenchymal electrode, and wherein positioning theelectrodes further comprises implanting at least one cerebrospinal fluid(CSF) electrode of the electrodes in a CSF-filled space of the brain,the CSF-filled space selected from a group consisting of: a ventricularsystem and a subarachnoid space, and wherein activating the controlcircuitry comprises activating control circuitry to drive theparenchymal and the CSF electrodes to apply the electrical current toenhance the microglial cell activation for taking up the substance fromthe brain parenchyma.
 8. The method according to claim 5, whereinimplanting the at least one of the electrodes comprises implanting theat least one of the electrodes in electrical contact with brainparenchyma.
 9. The method according to claim 8, wherein the at least oneof the electrodes is a parenchymal electrode, and wherein positioningthe electrodes further comprises implanting at least one cerebrospinalfluid (CSF) electrode of the electrodes in a CSF-filled space of thebrain, the CSF-filled space selected from a group consisting of: aventricular system and a subarachnoid space, and wherein activating thecontrol circuitry comprises activating control circuitry to drive theparenchymal and the CSF electrodes to apply the electrical current toenhance the microglial cell activation for taking up the substance fromthe brain parenchyma.
 10. The method according to claim 5, whereinimplanting at least one of the electrodes intracranially comprisesimplanting the at least one of the electrodes in a CSF-filled space ofthe brain, the CSF-filled space selected from a group consisting of: aventricular system and a subarachnoid space.
 11. The method according toclaim 1, wherein positioning the electrodes comprises positioning atleast one of the electrodes outside and in electrical contact with askull of the head.
 12. The method according to claim 1, whereinpositioning the electrodes comprises positioning at least one of theelectrodes on an external surface of skin of the head.
 13. The methodaccording to claim 1, wherein activating the control circuitry comprisesactivating the control circuitry to configure the electrical current tohave a frequency of between 10 and 90 Hz.
 14. The method according toclaim 1, wherein activating the control circuitry to configure theelectrical current to enhance the clearance of the substance from thebrain parenchyma to outside the brain parenchyma comprises activatingthe control circuitry to configure the electrical current to clear thesubstance from the brain parenchyma to a CSF-filled space of the brainselected from a group consisting of: a ventricular system and asubarachnoid space.
 15. A method comprising: positioning electrodes inor in contact with a head of a subject identified as in need of enhancedmicroglial cell activation; and activating control circuitry to drivethe electrodes to apply an electrical current to a brain of the subjectin pulses having an average pulse duration of between 0.1 ms and 10 ms,and to configure the electrical current to: enhance microglial cellactivation for taking up a substance from brain parenchyma, and enhanceclearance of the substance from brain parenchyma to outside the brainparenchyma, wherein the substance is selected from a group consistingof: amyloid beta and tau protein, wherein activating the controlcircuitry comprises activating the control circuitry to apply theelectrical current with an average amplitude of between 0.1 and 5 mA, orwith an average voltage that results in between 0.1 and 5 mA current,wherein activating the control circuitry to configure the electricalcurrent to enhance the microglial cell activation for taking up thesubstance from the brain parenchyma comprises activating the controlcircuitry to configure the electrical current as alternating current,and wherein activating the control circuitry to configure the electricalcurrent to enhance the clearance of the substance from the brainparenchyma to outside the brain parenchyma comprises activating thecontrol circuitry to configure the electrical current as direct current.16. The method according to claim 15, wherein activating the controlcircuitry comprises activating the control circuitry to apply theelectrical current in pulses with a duty cycle of between 1% and 50%.17. The method according to claim 15, wherein the substance is amyloidbeta, and wherein activating the control circuitry comprises activatingthe control circuitry to configure the electrical current to enhance themicroglial cell activation for taking up the amyloid beta from the brainparenchyma and to enhance the clearance of the beta amyloid from brainparenchyma to outside the brain parenchyma.
 18. The method according toclaim 15, wherein positioning the electrodes comprises positioning theelectrodes in or in contact with the head of a subject identified as atrisk of or suffering from Alzheimer's disease.
 19. The method accordingto claim 15, wherein positioning the electrodes comprises implanting atleast one of the electrodes intracranially.
 20. The method according toclaim 15, wherein positioning the electrodes comprises positioning atleast one of the electrodes outside and in electrical contact with askull of the head.
 21. The method according to claim 15, whereinpositioning the electrodes comprises positioning at least one of theelectrodes on an external surface of skin of the head.
 22. The methodaccording to claim 15, wherein activating the control circuitrycomprises activating the control circuitry to configure the electricalcurrent to have a frequency of between 10 and 90 Hz.
 23. The methodaccording to claim 15, wherein activating the control circuitry toconfigure the electrical current to enhance the clearance of thesubstance from the brain parenchyma to outside the brain parenchymacomprises activating the control circuitry to configure the electricalcurrent to clear the substance from the brain parenchyma to a CSF-filledspace of the brain selected from a group consisting of: a ventricularsystem and a subarachnoid space.
 24. A method comprising: positioningelectrodes in or in contact with a head of a subject identified as inneed of enhanced microglial cell activation; and activating controlcircuitry to drive the electrodes to apply an electrical current to abrain of the subject in pulses having an average pulse duration ofbetween 0.1 ms and 10 ms, and to configure the electrical current to:enhance microglial cell activation for taking up a substance from brainparenchyma, and enhance clearance of the substance from brain parenchymato outside the brain parenchyma, wherein the substance is selected froma group consisting of: amyloid beta and tau protein, wherein activatingthe control circuitry comprises activating the control circuitry toapply the electrical current with an average amplitude of between 0.1and 5 mA, or with an average voltage that results in between 0.1 and 5mA current, wherein activating the control circuitry to configure theelectrical current to enhance the microglial cell activation for takingup the substance from the brain parenchyma comprises activating thecontrol circuitry to configure the electrical current as direct current,and wherein activating the control circuitry to configure the electricalcurrent to enhance the clearance of the substance from the brainparenchyma to outside the brain parenchyma comprises activating thecontrol circuitry to configure the electrical current as direct current.25. The method according to claim 24, wherein the substance is amyloidbeta, and wherein activating the control circuitry comprises activatingthe control circuitry to configure the electrical current to enhance themicroglial cell activation for taking up the amyloid beta from the brainparenchyma and to enhance the clearance of the beta amyloid from brainparenchyma to outside the brain parenchyma.
 26. The method according toclaim 24, wherein positioning the electrodes comprises positioning theelectrodes in or in contact with the head of a subject identified as atrisk of or suffering from Alzheimer's disease.
 27. The method accordingto claim 24, wherein positioning the electrodes comprises implanting atleast one of the electrodes intracranially.
 28. The method according toclaim 24, wherein positioning the electrodes comprises positioning atleast one of the electrodes outside and in electrical contact with askull of the head.
 29. The method according to claim 24, whereinpositioning the electrodes comprises positioning at least one of theelectrodes on an external surface of skin of the head.
 30. The methodaccording to claim 24, wherein activating the control circuitrycomprises activating the control circuitry to configure the electricalcurrent to have a frequency of between 10 and 90 Hz.
 31. The methodaccording to claim 24, wherein activating the control circuitry toconfigure the electrical current to enhance the clearance of thesubstance from the brain parenchyma to outside the brain parenchymacomprises activating the control circuitry to configure the electricalcurrent to clear the substance from the brain parenchyma to a CSF-filledspace of the brain selected from a group consisting of: a ventricularsystem and a subarachnoid space.